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Substance use disorder: Epidemiology, medical consequences and treatment
Trastorno por uso de sustancias: epidemiología, complicaciones médicas y tratamiento
Daniel Fuster
Corresponding author
dfuster.germanstrias@gencat.cat

Corresponding author.
, Paola Zuluaga, Robert Muga
Unidad de Adicciones, Servicio de Medicina Interna, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Barcelona, Spain
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">In this narrative review&#44; we will discuss the main aspects of substance use disorder&#44; its epidemiology&#44; its main medical complications and how to treat it&#46; It is aimed at the lay practitioner and will focus on alcohol and other recreational drug use rather than tobacco use&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Overview</span><p id="par0010" class="elsevierStylePara elsevierViewall">The <span class="elsevierStyleItalic">Diagnostic and Statistical Manual of Mental Disorders</span> &#40;DSM&#41;-5 defines substance use disorder &#40;SUD&#41; as a set of 11 diagnostic criteria that include lack of control associated with substance use&#44; social impact of use&#44; risk associated with use&#44; and pharmacological criteria such as tolerance and dependence &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; and does not consider the legal consequences of use&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In patients with opioid use&#44; the presence of only the 2 pharmacological criteria would not be sufficient for the diagnosis of OUD &#40;opioid use disorder&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> SUD replaces what the DSM-IV-R defined as abuse and dependence or addiction&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> and addiction would equate to moderate or severe SUD&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> The new nomenclature uses less stigmatising and more patient-centred language&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> With the inclusion of craving&#44; it is possible that more patients meet DSM-5 diagnostic criteria for SUD than for abuse&#47;dependence according to DSM-IV-R&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">SUD would encompass those aberrant behaviours associated with the use of addictive substances that lead to alterations in brain activity and negative consequences for the patient&#39;s physical and emotional well-being&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> It causes lasting changes in brain physiology and permanent alteration of behaviour&#44; mediated by social&#44; psychological&#44; economic&#44; personal and family history&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Thus&#44; there is a heritability of 23&#37;&#8211;78&#37;&#44; associated with genetic polymorphisms&#44; but also with environmental factors such as early exposure or behavioural patterns in the family environment and circle of friends&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> Moreover&#44; not all substances have the same addictive potential&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> summarises the main phases in the natural history of SUD &#40;intoxication&#44; withdrawal and preoccupation&#47;anticipation&#41;&#44; characterised by neuro-adaptation&#44; behavioural changes and compulsive substance seeking&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Epidemiology</span><p id="par0025" class="elsevierStylePara elsevierViewall">SUD is a chronic and prevalent disease in the US&#44; 10&#46;2&#37; of the general population has alcohol use disorder &#40;AUD&#41; and 6&#46;6&#37; has AUD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> According to the EDADES 2022 study of the National Plan on Drugs&#44; the prevalence of use in the last 12 months among the Spanish population aged 15&#8211;64 is 76&#46;4&#37; for alcohol&#44; 39&#37; for tobacco&#44; 13&#46;1&#37; for sedative-hypnotics&#44; 10&#46;6&#37; for <span class="elsevierStyleItalic">cannabis</span> and 2&#46;4&#37; for cocaine powder and&#47;or base&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> 64&#46;6&#37; of the population have consumed alcohol in the last 30 days and 9&#37; consume alcohol daily&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> 16&#46;7&#37; reported getting drunk in the last 12 months&#44; and 15&#46;4&#37; reported binge-drinking in the last 30 days&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> The proportion of sedative-hypnotics use is higher in females &#40;16&#37;&#41; than in males &#40;10&#46;3&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">There is still a higher use of alcohol and other addictive substances among males&#44; although the proportion of females has increased in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> This is due to the greater stigma attached to substance use among women and its under-reporting&#44; especially in population-based surveys&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12</span></a> The imbalance is greater if we consider treatment admissions&#44; according to the National Plan on Drugs&#44; 80&#37; correspond to men and 20&#37; to women&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Alcohol is the first addictive substance for which treatment is sought in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Over the last 25 years&#44; heroin has gone from being the first illegal drug for which treatment is sought to the third&#44; after cocaine and <span class="elsevierStyleItalic">cannabis</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a><span class="elsevierStyleItalic">Cannabis</span> is the first substance for which treatment is sought in under-18s&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">The patient profile has changed in our setting&#59; from the opiate injector in the third to fourth decade of life&#44; with mainly infectious comorbidity &#40;at the expense of viral hepatitis and&#47;or HIV infection&#41; which was common until 2000&#44; to the middle-aged patient with AUD &#40;whether or not associated with other substance use&#41; and with high medical and psychiatric comorbidity&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;14</span></a> In the Detoxification Unit of the Germans Trias i Pujol University Hospital in Badalona &#40;Barcelona&#41;&#44; alcohol is the substance that most commonly leads to admission&#46; Alcohol is the substance that most commonly triggers a referral to the addiction unit for inpatient assessment in other departments&#59; and opiates are the second most common&#44; indicating that there is a niche of patients with intravenous heroin use who often need hospital admission for infectious complications&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> In our experience&#44; opiate use does not appear to be growing to US epidemic proportions&#44; where the number of opiate overdose deaths is 120&#44;000 per year&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In Spain&#44; the annual number of overdose deaths is less than 1000 and opiates are the second substance linked to these deaths after hypnosedatives&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Nor have we observed an increase in the number of new intravenous injectors&#44; accidental overdoses or soft tissue infections or right heart bacterial endocarditis&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> The number of patients on methadone has also remained stable in recent years&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p><p id="par0040" class="elsevierStylePara elsevierViewall">In terms of prescription of opioids for pain&#44; the most commonly prescribed opioids in Spain are tramadol &#40;62&#46;2&#37;&#41;&#44; fentanyl &#40;17&#46;5&#37;&#41; and buprenorphine &#40;6&#46;9&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> Fentanyl is mainly prescribed in the form of a transdermal patch&#44; with a much lower potential for misuse than other formulations&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> The prevalence of non-medical use of opioids for pain in Spain is 7&#37; in the last 12 months and 18&#37; in a lifetime&#44; with tramadol and codeine being the most used&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">Excessive alcohol consumption was responsible for more than 140&#44;000 deaths in the US during 2015&#8211;2019&#44; this is equivalent to more than 380 deaths per day&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a> In Spain&#44; between 2010&#8211;2017&#44; alcohol consumption accounted for 4&#37; of the overall risk of mortality&#44; especially premature deaths&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">Polydrug use has become the norm&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> In the US&#44; 64&#37; of substance misusing patients reported using a single substance&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> but only 26&#37; of those with at least 2 symptoms of SUD and only 22&#37; of those in treatment reported using a single substance&#46;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Complications arising from consumption</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Intoxications and acute complications</span><p id="par0055" class="elsevierStylePara elsevierViewall">Acute alcohol intoxication causes from language and memory impairment to agitation&#44; seizures and&#44; in more severe cases&#44; decreased consciousness with respiratory depression&#46; Other possible disorders include lactic acidosis&#44; hypoglycaemia&#44; hypocalcaemia with hypomagnesaemia and hypophosphataemia&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> Pancreatitis and steatohepatitis or atrial fibrillation are acute complications that can occur after high intake&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> In patients with or without previous liver disease&#44; an episode of acute alcoholic hepatitis can be precipitated&#44; a serious complication with a high risk of infections&#44; liver failure and death&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Wernicke&#8217;s encephalopathy is the most relevant acute neuropsychiatric complication in patients with chronic alcohol consumption&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Its prevalence is underestimated as few patients present with the classic triad &#40;ophthalmoparesis&#44; ataxia and confusion&#41; and its symptoms may overlap with those of <span class="elsevierStyleItalic">delirium tremens</span> &#40;most extreme form of alcohol withdrawal&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Early treatment with thiamine often improves symptomatology and may prevent complications&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">Psychostimulant intoxication &#40;cocaine&#44; amphetamines and derivatives&#41; symptoms are due to the massive release of dopamine and norepinephrine&#44; and typically range from psychomotor agitation to tonic-clonic seizures followed by coma&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The most common symptoms include palpitations&#44; tachycardia&#44; chest pain&#44; muscle spasms&#44; hyperthermia&#44; headache&#44; tachypnoea&#44; anxiety and delirium&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Cardiovascular complications of acute cocaine intoxication can be severe&#44; ranging from high blood pressure and tachycardia to cardiac arrhythmias&#44; acute coronary syndrome&#44; myocarditis&#44; acute pulmonary oedema and aortic dissection&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Other complications include acute urinary retention or acute renal failure with or without associated rhabdomyolysis&#46; Less common are ischaemic colitis&#44; pseudomembranous colitis and intestinal ischaemia&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">30</span></a> Respiratory manifestations&#44; related to smoked cocaine base use&#44; range from lip burns and upper airway inflammation to bronchospasm&#44; acute pulmonary oedema&#44; haemoptysis&#44; interstitial pneumonitis and alveolar haemorrhage&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">MDMA use may promote a serotonergic syndrome&#44;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> with hyperactivity&#44; mental confusion&#44; hyperreflexia&#44; hyperthermia&#44; agitation&#44; diarrhoea&#44; myoclonus and tremor&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a> MDMA and cocaine use has been associated with cases of acute hepatitis of variable severity&#44;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> probably related to the toxic effect of unidentified liver metabolites&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Cannabis</span> use rarely causes severe symptoms with intoxication&#46; Symptoms are similar to the pharmacological effects&#44; although more pronounced&#59; with motor incoordination&#44; impaired judgement&#44; anxiety or panic&#44; conjunctival injection&#44; increased appetite&#44; xerostomia and tachycardia&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Delirium or psychosis may occur&#44; although less frequently&#46; Accidental poisoning of edible forms in children may be more severe and may include stupor&#44; coma&#44; hypotension and hypothermia&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Concomitant use with alcohol enhances the depressant effect on the central nervous system&#46; In countries where <span class="elsevierStyleItalic">cannabis</span> use has been legalised&#44; road traffic accidents and accidental poisoning in minors have increased&#46;<a class="elsevierStyleCrossRef" href="#bib0175"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">The main and most relevant effect of opioids and benzodiazepines is sedation&#44; which in more severe cases involves respiratory centre depression&#44; more intense in the case of opioids&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> At high doses&#44; they can cause peripheral vasodilatation&#44; hypotension and bradycardia&#44; and even death due to respiratory depression&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">The main symptoms of withdrawal from addictive substances and their potential treatment are summarised in <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#46; It is important to identify patients at risk of alcohol withdrawal syndrome&#44; as it has a high mortality rate if not recognised early and treated appropriately&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chronic complications of addictive substance use</span><p id="par0090" class="elsevierStylePara elsevierViewall">Liver disease is the most common medical condition associated with alcohol consumption&#44; even at low doses in susceptible patients&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Nearly 90&#37; of patients with AUD will develop steatosis&#44; potentially reversible with alcohol abstinence&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Liver involvement also includes steato-hepatitis&#44; liver fibrosis&#44; cirrhosis and hepatocellular carcinoma&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Acute alcoholic hepatitis can occur at any of these histological stages&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Overweight&#44; obesity&#44; diabetes mellitus&#44; hepatitis C virus infection&#44; smoking and predisposing genetic factors have been associated with histological forms with worse prognosis&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> Concomitant use of alcohol and cocaine increases the oxidative activity of cytochrome CYP450&#44; favouring the production of toxic metabolites such as cocaethylene and promoting mitochondrial toxicity&#44; which has been linked to increased progression of liver disease&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">Chronic cocaine and alcohol use are associated with cardiovascular disease&#46; Alcohol has effects on the autonomic nervous system and the renin angiotensin axis&#44; increasing baroreceptor sensitivity and calcium influx into smooth muscle cells&#46; Cocaine acts on the adrenergic and dopaminergic system&#44; promotes platelet aggregation and endothelial damage through direct toxicity&#46; As a consequence&#44; peripheral vascular resistance&#44; myocardial contractility&#44; heart rate and blood pressure increase&#44; with increased myocardial oxygen demand&#44; which is not met by vasoconstriction&#46; Medical comorbidity includes hypertension&#44; ischaemic or haemorrhagic stroke&#44; supraventricular arrhythmias&#44; heart failure&#44; coronary heart disease&#44; peripheral arterial disease&#44; abdominal aortic aneurysms&#44; dilated cardiomyopathy and sudden death&#46;<a class="elsevierStyleCrossRefs" href="#bib0185"><span class="elsevierStyleSup">37&#44;38</span></a> Additionally&#44; the presence of cocaethylene causes prolonged myocardial depression&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Intranasal cocaine use is associated with chronic rhinitis and perforation of the nasal septum&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Chronic use of alcohol&#44; methamphetamines and MDMA is associated with neurological disorders&#46; Cerebellar ataxia is the most common in alcohol consumption&#44; affecting 10&#37;&#8211;25&#37; of patients with AUD&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> characterised by a gait with increased base of support&#44; but with a relative absence of lower limb ataxia or other cerebellar signs&#44; such as nystagmus or dysarthria&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> Korsakoff&#8217;s psychosis&#44; characterised by permanent neurological damage&#44; is a complication occurring in 20&#37; of cases of Wernicke&#39;s encephalopathy&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> with retrograde and anterograde memory impairment&#44; executive dysfunction&#44; apathy&#44; lack of illness awareness and daydreaming&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Chronic alcohol consumption is also associated with cognitive impairment and Marchiava&#8211;Bignami syndrome&#44; a degenerative demyelinating disease of the corpus callosum&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> The difficulty in differentiating between these entities in routine clinical practice has given rise to the term <span class="elsevierStyleItalic">alcohol-related brain injury</span> &#40;ARBI&#41;&#44; or alcohol-related brain injury&#46; Alcohol affects the peripheral nervous system&#44; with longitudinal-dependent sensory polyneuropathy that in its most severe forms has motor manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">Chronic use of methamphetamines and MDMA causes neuronal damage<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a> and altered serotonergic function in the cerebral cortex and hippocampus&#44; with depression&#44; impaired sleep and pain perception and changes in sexual function&#46;<a class="elsevierStyleCrossRef" href="#bib0160"><span class="elsevierStyleSup">32</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Medical complications of chronic opiate use are related to the effects exerted on opiate receptors&#44; causing constipation&#44; urinary retention&#44; reduced macrophage phagocyte function&#44; increased growth hormone secretion and reduced sex hormones&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> There are also intravenous consumption-related complications&#44; such as HCV&#44; HBV and&#47;or HIV infection&#44; skin and soft tissue infections&#44; bone and joint infections due to haematogenous spread and right heart bacterial endocarditis with potential lung or splenic abscesses&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;13</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Chronic use of <span class="elsevierStyleItalic">cannabis</span> leads to fewer medical complications than other substances&#44; but respiratory symptoms such as chronic bronchitis and rhino-sinusitis and&#47;or bronchospasm<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> are of particular relevance&#46; It is also a risk factor for lung cancer&#44; spontaneous pneumothorax&#44; bullous emphysema and chronic obstructive pulmonary disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">42&#44;43</span></a> Another complication&#44; especially in individuals with high intakes&#44; is cannabinoid hyperemesis syndrome&#44; characterised by vomiting that only subsides on exposure to hot water and may be associated with dehydration and &#8216;pre-renal&#8217; renal failure&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall">SUD is associated with psychiatric comorbidity&#46; Anxiety and post-traumatic stress disorders&#44; depressive disorders&#44; bipolar disorder and schizoaffective disorder are common among AUD patients&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> In general&#44; the coexistence of AUD and mental disorder is associated with worse prognosis&#44; poorer adherence to treatment and higher rates of depression&#44; suicide and relapse&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a> Cannabis use disorder &#40;CUD&#41; is often associated with attention deficit hyperactivity disorder and lower academic or career success&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;46</span></a> There is controversy about the risk of developing psychosis in early <span class="elsevierStyleItalic">cannabis</span> smokers&#44; as it is possible that these children are systematically different from their non-using peers in terms of predisposing factors for mental illness&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Chronic use of <span class="elsevierStyleItalic">cannabis</span> is associated with non-specific cognitive impairments&#44; affecting short-term memory&#44; planning&#44; comprehension and reasoning skills&#44; as well as with amotivational syndrome and depressive disorders&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0125" class="elsevierStylePara elsevierViewall">The use of cocaine&#44; <span class="elsevierStyleItalic">cannabis</span>&#44; opiates and alcohol has immunomodulatory effects that predispose to bacterial and viral infections&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Thus&#44; there is a lower probability of spontaneous clearance and higher HCV replication in patients with alcohol consumption&#44; as well as an increased risk of respiratory infections&#44; mostly linked to aspiration of oropharyngeal contents or <span class="elsevierStyleItalic">Legionella pneumophila</span> and <span class="elsevierStyleItalic">Mycobacterium tuberculosis</span> infections&#46;<a class="elsevierStyleCrossRefs" href="#bib0065"><span class="elsevierStyleSup">13&#44;47</span></a> Substance use in HIV patients is associated with increased progression of infection&#44; lower CD4 count&#44; reduced immune recovery&#44; reduced adherence to antiretroviral treatment and increased social marginalization&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">Alcohol is also a carcinogen and its consumption has been associated with cancers of the lip&#44; oral cavity&#44; pharynx&#44; larynx&#44; stomach&#44; colorectal cancer&#44; hepatocarcinoma and breast cancer in women&#44; even at doses that might be considered moderate&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">A summary of the complications associated with the most prevalent addictive substance use is shown in <a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Treatment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Despite the negative health consequences&#44; there is a significant group of patients who do not receive a proper diagnosis of SUD or AUD&#44; and of those who do&#44; only a minority receive specific treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> It is therefore essential to implement screening&#44; brief intervention and referral to treatment &#40;SBIRT&#41; in primary care&#44; hospital emergency departments&#44; inpatient areas and in internal medicine outpatient care&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> All patients assessed in a clinical setting should be screened in a systematic way&#59; using questions such as &#8220;How many times in the past year have you had X or more drinks &#40;equivalent to 10&#8239;g of pure alcohol&#41; in a day&#63;&#8221; where X corresponds to 5 for males and 4 for females for harmful use of alcohol<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> and &#8220;How many times in the last year have you used an illegal drug or a prescription medication for non-medical reasons&#8221; for other drug use<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&#46; Patients who screen positive&#44; i&#46;e&#46; answer one or more times&#44; will require further investigation&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> The use of brief intervention has been shown to be effective for harmful alcohol use that does not meet AUD criteria&#44;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> while its effectiveness for harmful drug use is debated&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">Access to treatment is inadequate&#44; even in Western countries with public health systems&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> This is due to waiting times for some resources and inadequate identification of patients eligible for treatment in clinical settings or on release from prison&#46; It is estimated that 25&#37; of hospitalised patients present with AUD or SUD&#44; implying increased co-morbidity and clinical complications during admission&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Hospital admission is an opportunity to identify SUD&#44; to initiate treatment and linkage to clinical management&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> as well as to increase trust in the health care system&#44; reduce the severity of SUD and mitigate stigma&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Pharmacological treatments for AUD and OUD are effective&#44; and can be initiated during hospital admission&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;52</span></a> Patients with AUD are more likely to be linked to out-of-hospital treatment if they receive a brief intervention during hospitalization&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Initiation of treatment during hospitalisation or emergency care is associated with lower consumption&#44; better retention in treatment and fewer hospital readmissions&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> The small number of patients who start buprenorphine or methadone treatment after a non-fatal overdose have lower medium-term mortality&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Health professionals feel ill-equipped to detect&#44; diagnose and treat SUD&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> To this end&#44; it is essential to improve their training&#44; or to have teams of doctors with sufficient expertise in SUD&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> Stigma also results in patients with AUD or SUD being treated worse than other patients with chronic diseases&#44; which perpetuates the sense of healthcare system mistreatment experienced by these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">Withdrawal syndrome treatment may be a gateway to long-term treatment of SUD&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Therefore&#44; a hospitalisation or a visit to the emergency department may be a good time to inform the patient about treatment options&#44; as it is often many years between the onset of harmful use and the time when the patient seeks help&#46; So-called <span class="elsevierStyleItalic">&#8220;bridge clinics&#8221;</span> have been created to improve accessibility to treatment<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a>&#59; they have a low threshold in their admission criteria and serve as a transition while patients await long-term resources&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Similarly&#44; at the Addictions Unit of the Germans Trias i Pujol University Hospital&#44; we schedule an outpatient visit for all patients seen during hospitalisation&#44; both for detoxification and for those assessed interdisciplinary&#44; to monitor clinical progress and detect early on a potential relapse in consumption&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">It is essential to design patient-centred and harm minimisation strategies&#44; especially for those patients who are in a pre-contemplation phase and do not want to stop substance use in order to avoid negative consequences&#46; Harm minimisation would include needle&#47;syringe programmes&#44; safe injection and overdose prevention rooms&#44; as well as supervised alcohol intake in highly selected patients&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> Safe opioid prescribing rules for chronic pain patients are essential to expose as few patients as possible to opioid misuse&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Treatment includes information&#44; education&#44; recognition and acceptance of the diagnosis&#44; detoxification and pharmacological and non-pharmacological treatment to prevent relapse once abstinence has been achieved&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> It is important to provide information on the nature of SUD&#44; and on its medical&#44; psychiatric and social complications&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> If the patient relapses&#44; it is likely that he&#47;she will return to a consumption similar to that prior to detoxification&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Detoxification is the first step necessary for treatment to begin&#46; It is medically supervised withdrawal and can be either outpatient or inpatient&#46; Inpatient detoxification is reserved for patients with high consumption&#44; with increased comorbidity&#44; with previous outpatient detoxification failures or with a history of severe complications such as seizures or <span class="elsevierStyleItalic">delirium</span>&#46; After detoxification&#44; which usually lasts between one week and 10 days&#44; habit-breaking begins&#44; which would cover the first year of treatment&#44; a time when there is a greater risk of relapse&#46; Evidence-based pharmacological and non-pharmacological treatment &#40;individual and group therapy&#41; is also important&#44; with special emphasis on cognitive&#8211;behavioural therapy&#46; There are third-generation therapies&#44; such as mindfulness-based therapies and acceptance and commitment therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">57</span></a> There is also promising data on the use of psychedelic drugs&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> The role that regular urine drug and&#47;or alcohol screening and 12-step programmes such as alcoholics or narcotics anonymous can play in a multidimensional therapeutic approach should not be overlooked&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Self-reporting is a useful tool in the follow-up of patients with SUD&#44; however&#44; its accuracy may be low in the follow-up of patients where abstinence is a requirement&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> Substances can be detected in urine&#46; Novel direct biomarkers of alcohol metabolism&#44; such as carbohydrate-deficient transferrin&#44; ethyl glucuronide&#44; ethyl sulphate and phosphatidyl ethanol&#44; can be used to estimate alcohol consumption in the last 2&#8211;4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">In Europe there are 4 drugs accepted by regulatory agencies for the treatment of AUD&#59; disulfiram&#44; acamprosate&#44; naltrexone and nalmefene&#44; described in <a class="elsevierStyleCrossRef" href="#tbl0025">Table 5</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The aim of nalmefene treatment would be to reduce alcohol intake in those patients with harmful drinking who do not meet AUD criteria and would not be indicated for those patients where the aim of treatment is abstinence&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The goal of treatment with the other 3 is the prevention of relapse<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> and the involvement of liver biology may make their use difficult&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><elsevierMultimedia ident="tbl0025"></elsevierMultimedia><p id="par0190" class="elsevierStylePara elsevierViewall">There are 3 drugs approved for the treatment of OUD&#44; namely methadone&#44; buprenorphine and naltrexone&#44; described in <a class="elsevierStyleCrossRef" href="#tbl0030">Table 6</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are other therapeutic options used in other geographical areas&#44; such as treatment with diacetylmorphine in safe injection rooms &#40;Switzerland&#41; or with other oral morphine formulations &#40;Austria&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Pharmacological treatment for OUD is associated with beneficial effects&#44; such as reduced risk of death from overdose&#44; lower rates HIV or HCV infections&#44; and reduced social impact of use&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The decline in opiate use observed in our setting has been largely due to the availability of methadone treatment and the availability of other harm reduction resources&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> Methadone treatment in Spain tends to have a low threshold&#44; and patients are only excluded if they are violent&#44; using or dealing in the vicinity of the treatment area&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> More than 60&#37; of patients with OUD undergo pharmacological treatment in Spain&#46;<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a></p><elsevierMultimedia ident="tbl0030"></elsevierMultimedia><p id="par0195" class="elsevierStylePara elsevierViewall">In contrast&#44; there are no approved pharmacological treatments for the other most prevalent SUDs&#44; such as CUD or stimulants &#40;cocaine and&#47;or amphetamines&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> leading to the use of off-label drugs to reduce impulsivity &#40;topiramate&#44; gabapentin&#41; or craving &#40;bupropion&#44; atypical antipsychotics&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Ethical considerations</span><p id="par0200" class="elsevierStylePara elsevierViewall">As this was a narrative review and did not include patient information&#44; informed consent was not required&#46;</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Funding</span><p id="par0205" class="elsevierStylePara elsevierViewall">This review has been partially funded by the <span class="elsevierStyleGrantSponsor" id="gs0005">Ministry of Science and Information</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0010">Instituto de Salud Carlos III</span> &#40;RETICS RD16&#47;0017&#47;0003&#44; Juan Rodes Programme JR20&#47;00016&#44; Sara Borrell Programme CD19&#47;00019&#44; grant PI20&#47;00883 and Redes de Investigaci&#243;n Cooperativa Orientadas a Resultados en Salud &#40;RICORS&#41;-Red de Investigaci&#243;n en Atenci&#243;n Primaria de Adicciones &#40;RIAPAd&#41;&#44; grant RD21&#47;0009&#47;0004&#41;&#44; <span class="elsevierStyleGrantSponsor" id="gs0015">European Fund for Regional Development</span> &#40;FEDER&#41;&#59; the <span class="elsevierStyleGrantSponsor" id="gs0020">Ministry of Health&#44; National Plan on Drugs</span> &#40;grant <span class="elsevierStyleGrantNumber" refid="gs0020">2020&#47;024</span>&#41; and by the <span class="elsevierStyleGrantSponsor" id="gs0025">Generalitat de Catalunya</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs0030">Consolidated Research Group</span> &#40;<span class="elsevierStyleGrantNumber" refid="gs0030">2021-SGR-00945</span>&#41;&#59; all in Spain&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conflict of interest</span><p id="par0210" class="elsevierStylePara elsevierViewall">There are no conflicts of interest to mention&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
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        1 => array:2 [
          "identificador" => "xpalclavsec1824900"
          "titulo" => "Keywords"
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          "titulo" => "Epidemiology"
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        7 => array:3 [
          "identificador" => "sec0020"
          "titulo" => "Complications arising from consumption"
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            0 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Intoxications and acute complications"
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        8 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Chronic complications of addictive substance use"
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          "titulo" => "Treatment"
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    "fechaAceptado" => "2023-11-08"
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          "palabras" => array:9 [
            0 => "Substance use disorder"
            1 => "Alcohol"
            2 => "Opiates"
            3 => "Cocaine"
            4 => "<span class="elsevierStyleItalic">Cannabis</span>"
            5 => "Benzodiazepines"
            6 => "Epidemiology"
            7 => "Medical consequences"
            8 => "Treatment"
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          "clase" => "keyword"
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          "identificador" => "xpalclavsec1824899"
          "palabras" => array:9 [
            0 => "Trastorno por uso de sustancias"
            1 => "Alcohol"
            2 => "Opi&#225;ceos"
            3 => "Coca&#237;na"
            4 => "<span class="elsevierStyleItalic">Cannabis</span>"
            5 => "Benzodiacepinas"
            6 => "Epidemiolog&#237;a"
            7 => "Complicaciones m&#233;dicas"
            8 => "Tratamiento"
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    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0060" class="elsevierStyleSimplePara elsevierViewall">Substance use is a common health problem&#44; and substance use disorder&#44; which is its most severe presentation&#44; is associated with multiple medical consequences and a negative impact on individual and on population health&#46; Substance use disorder needs to be addressed as any chronic medical condition&#59; therefore&#44; it has to be detected at the early stages and has to be properly treated to prevent drug-related harm&#46; Internists should be able to recognize and treat intoxication and abstinence&#46; Internists should also be able to refer the patient to state of the art long term treatment&#44; aimed to detoxification and treatment induction to promote abstinence and prevent relapse&#46; In this narrative review we will discuss substance use epidemiology&#44; its main medical consequences and its treatment&#44; with a focus on alcohol&#44; opiates&#44; cocaine and other stimulants&#44; <span class="elsevierStyleItalic">cannabis</span> and benzodiazepines&#46;</p></span>"
      ]
      "es" => array:2 [
        "titulo" => "Resumen"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0065" class="elsevierStyleSimplePara elsevierViewall">El consumo de sustancias adictivas es un problema de salud prevalente&#44; que en su forma m&#225;s extrema&#44; el trastorno por uso de sustancias&#44; se asocia con consecuencias m&#233;dicas que tienen un impacto negativo en la salud&#44; tanto individual como poblacional&#46; El trastorno por uso de sustancias debe ser abordado como cualquier otra enfermedad cr&#243;nica&#59; as&#237;&#44; ha de ser identificado de forma precoz y debe ser adecuadamente tratado para evitar consecuencias futuras&#46; El m&#233;dico internista est&#225; capacitado para reconocer y tratar las consecuencias inmediatas de la intoxicaci&#243;n o la abstinencia&#46; Tambi&#233;n ha de remitir al paciente a recibir un tratamiento adecuado&#44; tanto de desintoxicaci&#243;n como para mantener la abstinencia y evitar la reca&#237;da en el consumo&#46; En esta revisi&#243;n narrativa discutiremos la epidemiolog&#237;a&#44; las principales complicaciones del consumo perjudicial y el tratamiento m&#225;s adecuado del trastorno por uso de sustancias&#44; con &#233;nfasis especial en el alcohol&#44; opi&#225;ceos&#44; coca&#237;na y otros estimulantes&#44; <span class="elsevierStyleItalic">cannabis</span> y benzodiacepinas&#46;</p></span>"
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          "leyenda" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">2&#8211;3 criteria&#58; mild SUD&#59; 4&#8211;6 criteria&#58; moderate SUD&#59; &#62;6 criteria&#58; severe SUD&#46;</p>"
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                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleBold">There are 4 criteria groups&#58;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A&#41; Lack of control over substance use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>1&#46; Taking the substance in larger amounts or for longer than you are meant to&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>2&#46; Wanting to cut down or stop using the substance but not managing to&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>3&#46; Spending a lot of time getting&#44; using&#44; or recovering from use of the substance &#40;in the most severe cases the person&#8217;s daily activities may revolve around the substance&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>4&#46; Cravings and urges to use the substance&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">B&#41; Social impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>5&#46; Not managing to do what you should at work&#44; home&#44; or school because of substance use&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>6 Continuing to use&#44; even when it causes problems in relationships&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>7&#46; Giving up important social&#44; occupational&#44; or recreational activities because of substance use&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C&#41; Risky use of substance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>8&#46; Using substances again and again&#44; even when it puts you in danger&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>9&#46; Continuing to use&#44; even when you know you have a physical or psychological problem that could have been caused or made worse by the substance&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">D&#41; Pharmacological criteria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>10&#46; Needing more of the substance to get the effect you want &#40;tolerance&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>11&#46; Development of withdrawal symptoms&#44; which can be relieved by taking more of the substance&#46;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Criteria for substance use disorder according to DSM-5&#46;</p>"
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          "leyenda" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">CRH&#58; corticotropin-releasing hormone&#59; SUD&#58; substance use disorder&#46;</p>"
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                  <table border="0" frame="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">SUD Phase&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main characteristics&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Neurotransmitters involved&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Anatomical area involved&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Intoxication</td><td class="td" title="\n
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                  \t\t\t\t">Positive reinforcement for the effects of the substance and the stimuli associated with its use</td><td class="td" title="\n
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                  \t\t\t\t">Dopamine&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Nucleus <span class="elsevierStyleItalic">accumbens</span>&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Endogenous opioids&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dorsal striatum&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Withdrawal</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative emotional state&#46; Anti-reward circuits are predominant&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Norepinephrine dynorphin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amygdala</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CRH&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preoccupation&#47;anticipation</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Addictive substance use anxiety</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Glutamate</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Basolateral tonsil&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hippocampus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prefrontal cortex&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
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        "descripcion" => array:1 [
          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">SUD neuroadaptation phases&#46;</p>"
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      2 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at0015"
            "detalle" => "Table "
            "rol" => "short"
          ]
        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">CNS&#58; central nervous system&#59; HBV&#58; hepatitis B virus&#59; HCV&#58; hepatitis C virus&#59; HIV&#58; human immunodeficiency virus&#59; IV&#58; intravenous&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Addictive substance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Acute complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Chronic complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="12" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Language impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol-associated liver disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Lack of coordination&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chronic pancreatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Memory impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Wernicke&#8211;Korsakoff&#8217;s encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreased level of consciousness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebellar degeneration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nausea and vomiting&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcoholic polyneuropathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Acute pancreatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dyselectrolytemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol-associated acute hepatitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Megaloblastic anaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dyselectrolytemia</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cardiomyopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Atrial fibrillation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased risk of infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Carcinogenic effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="9" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Opioids</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Miosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IV consumption&#58;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Analgesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8226; HCV and&#47;or HBV infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peripheral vasodilatation&#46; Hypotension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8226; HIV infection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bradycardia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8226; Endocarditis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="5" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Life-threatening respiratory depression</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>&#8226; Soft-tissue abscesses&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hypogonadism&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Osteoporosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased risk of infections&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chronic pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="18" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cocaine-psycho-stimulants</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anxiety&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Nasal septum perforation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insomnia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rhabdomyolysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tachycardia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kidney failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Arterial hypertension&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myocardial ischaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pupillary dilation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aortic dissection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sweating&#44; chills&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Malignant hyperthermia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tremor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vasculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Confusion&#44; convulsions&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intestinal ischaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Chest pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Respiratory disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Vasoconstriction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decompensation psychiatric disorders&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rhabdomyolysis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Kidney failure&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sleep disturbance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Myocardial ischaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Altered perception of pain&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Aortic dissection&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Changes in sexual function&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ictus&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Seizures&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Subarachnoid haemorrhage&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sudden death</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intestinal ischaemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sudden death&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cannabis</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anxiety disorder&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amotivational syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tachycardia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Depression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Increased appetite&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreased attention and memory&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hallucinosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Effects on the respiratory system&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disorientation</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cannabinoid</span> hyperemesis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Headache&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzodiazepines&#47;sedative-hypnotics</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Deep sleep without respiratory centre depression or cardiovascular disturbance&#46; Increased risk in concomitant use of other CNS depressants &#40;alcohol&#44; opiates&#41;&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Drowsiness&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Confusion&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysphoria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blurred vision&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Coordination impairment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Amnesia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Substance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Symptomatology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alcohol<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">It is quantified with the <span class="elsevierStyleItalic">Clinical Institute Withdrawal Assessment scale for Alcohol-revised</span> &#40;CIWAr&#41;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">CIWAr values &#60;8 do not require pharmacological treatment&#44; and values &#60;15 without seizures or <span class="elsevierStyleItalic">delirium tremens</span> can be treated as outpatient<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild forms&#58; distal tremor&#44; hyperactivity of the autonomic system&#44; tachycardia&#44; hypertension&#44; diaphoresis&#44; fever or psychomotor agitation&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzodiazepines&#58; fixed or symptom-triggered regimen<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Delirium tremens</span> &#40;most extreme form&#41;&#58; zoopsia&#44; perception&#44; language&#44; memory and orientation disturbances&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a> 10&#37; mortality due to severe water-electrolyte imbalance&#44; hyperthermia&#44; cardiac arrhythmias and convulsions<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">27</span></a></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gabapentin in mild forms<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Alpha-blockers for sympathomimetic symptomatology<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Opioids</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anxiety&#44; dysphoria&#44; nausea and vomiting&#44; watering eye&#44; yawning&#44; piloerection&#44; increased body temperature and mydriasis<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Methadone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Heroin&#58; onset at 24&#8211;36&#8239;h and duration of one week&#46; Methadone&#58; start at 48&#8211;72&#8239;h and duration of 2 weeks<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">51</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Buprenorphine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cocaine and psychostimulants</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anhedonia&#44; lethargy&#44; anxiety&#44; altered biorhythms and high carbohydrate intake&#46;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzodiazepines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Olanzapine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="4" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Cannabis</span></td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Irritability&#44; aggressiveness&#44; restlessness&#44; anxiety&#44; anorexia&#44; tremor&#44; sweating&#44; diarrhoea and increased tendon reflexes&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzodiazepines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Start&#58; 24&#8211;48&#8239;h after cessation of use&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Symptomatic treatment &#40;metoclopramide if nausea&#44; paracetamol&#41;</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Peak symptomatology&#58; 4&#8211;6 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Duration&#58; 21&#8211;30 days&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Benzodiazepines&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Tremors&#44; anxiety&#44; perception disorders&#44; dysphoria and in severe cases psychosis and convulsions&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reintroduction of benzodiazepine treatment and gradual withdrawal over weeks or months<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "notaPie" => array:2 [
            0 => array:3 [
              "identificador" => "tblfn0005"
              "etiqueta" => "a"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Increased risk in older age&#44; several previous detoxification attempts or a history of alcohol withdrawal&#46;</p>"
            ]
            1 => array:3 [
              "identificador" => "tblfn0010"
              "etiqueta" => "b"
              "nota" => "<p class="elsevierStyleNotepara" id="npar0010">Strategy also valid for the treatment of benzodiazepine use disorder&#46; As a harm minimisation strategy&#44; the dose can be lowered&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Symptomatology and treatment of the main addictive substance withdrawal syndromes&#46;</p>"
        ]
      ]
      4 => array:8 [
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        "etiqueta" => "Table 5"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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        "detalles" => array:1 [
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            "identificador" => "at0025"
            "detalle" => "Table "
            "rol" => "short"
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        ]
        "tabla" => array:2 [
          "leyenda" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">im&#58; Intramuscular&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Drugs approved by regulatory agencies</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead rowgroup " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Naltrexone</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">50&#8239;mg&#47;day &#40;oral&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Avoid in decompensated cirrhosis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">380&#8239;mg per month &#40;via im&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicated in opioid-treated patients&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Acamprosate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">666&#8239;mg every 8&#8239;h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicated in creatinine filtration rate &#60;30&#8239;mg&#47;day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Disulfiram&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">250&#8211;500&#8239;mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Contraindicated in cirrhosis&#46; Most effective in directly observed therapy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Nalmefene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">18&#8239;mg on demand&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Not suitable if abstinence is the therapeutic goal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Unapproved drugs</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Gabapentin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">900&#8211;1800&#8239;mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Suitable option if the patient has polyneuropathy&#46; Substance with addictive potential&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Topiramate&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">300&#8239;mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Its side effects are similar to hepatic encephalopathy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Ondansetron&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&#8211;16&#8239;&#181;g per kg of weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Potentially hepatotoxic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Baclofen&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&#8239;mg&#47;each 8&#8239;h&#46; Avoid &#62;80&#8239;mg doses per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common off-label use in France&#46; Recommended by Hepatology Societies despite conflicting results on its efficacy&#46; High doses associated with higher risk of death in pharmacovigilance studies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Varenicline&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8239;mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Limited experience&#44; potential smoking cessation effect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Pharmacological treatment for alcohol use disorder&#46;</p>"
        ]
      ]
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        "etiqueta" => "Table 6"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0055" class="elsevierStyleSimplePara elsevierViewall">im&#58; Intramuscular&#59; QTc&#58; QT corrected&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Dose&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Considerations&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Drugs approved by regulatory agencies</span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Methadone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Doses higher than 60&#8239;mg per day are recommended&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">QTc interval monitoring is recommended&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Buprenorphine&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#8211;24&#8239;mg per day&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Risk of precipitating withdrawal if started too early&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Buprenorphine&#47;naloxone&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&#47;0&#44;5&#8239;mg&#8211;24&#47;6&#8239;mg&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Risk of precipitating withdrawal if started too early&#46; Not funded by the Spanish Health System&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Naltrexone</td><td class="td" title="\n
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                  \t\t\t\t">50&#8239;mg&#47;day &#40;oral&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t">Risk of precipitating withdrawal if started too early&#46; For highly motivated patients&#46; Lower efficacy than methadone or buprenorphine&#46; Only option in countries without opioid agonist treatment</td></tr><tr title="table-row"><td class="td-with-role" title="\n
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                  \t\t\t\t">380&#8239;mg per month &#40;im&#41;&nbsp;\t\t\t\t\t\t\n
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ISSN: 23870206
Original language: English
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos