21 August 2008

Lofexidine for withdrawal symptoms works ... (but detoxification usually doesn't).

A Phase 3 placebo-controlled, double-blind, multi-site trial of the alpha-2-adrenergic agonist, lofexidine, for opioid withdrawal. Yu E, Miotto K, Akerele E, Montgomery A, Elkashef A, Walsh R, Montoya I, Fischman MW, Collins J, McSherry F, Boardman K, Davies DK, O�Brien CP, Ling W, Kleber H, Herman BH. Drug and Alcohol Dependence 2008 97;1-2:158-168

Dear Colleagues,
This may be a world record for delays in clinical research. Dr Kleber first wrote about the possible effectiveness of lofexidine for withdrawals in 1981 (ref 1). Now, with a stellar cast of senior American colleagues he has produced a small and unsatisfactory report (n = 68, only 17 completers) in the course of attempting to have the drug registered in the United States. With modest but apparently significant benefits noted in a 4 day regimen using the drug, the trial was dramatically called off just over half way thru. This is normally only done where it is considered unethical to continue to using placebo. However those receiving lofexidine also suffered 4 significant side effects, each probably related to hypotension. The benefit of lofexidine was a reduction in withdrawal symptoms/signs from 30 to 20 and an increase in retention from 15 to 38%. While these differences are substantial, the same or better might have been obtained with clonidine, diazepam or even �hospital brandy�. Additionally we know that this intervention (detoxification from opioids) has a ~90% failure rate and also a substantial mortality in the period following.

Doctors and health workers can recommend established, effective treatments, yet detoxification should only be initiated by the patient in my view � both due to its inherent dangers and the lack of a proven strategy to achieve this noble goal. It is hard to justify detoxification from opioids in pregnancy, for example, and some would say it is unethical. On the other hand, patients are perfectly entitled to request services which doctors would not normally actively recommend (abortion, contraception, euthanasia, circumcision, etc). As long as the detoxification is patient-initiated, and the patients are aware of the alternatives and the relative risks then there can be no ethical problem.

The authors give a comprehensive literature review, pointing out that there is little current evidence favouring lofexidine over clonidine regarding effectiveness yet the former seems to have less hypotensive side effects in some trials. Some quoted trials compared lofexidine with buprenorphine, a ludicrous comparison in my view. It would be like comparing aspirin with penicillin for bronchitis. So after 25 years I am still not convinced that lofexidine is a sure-thing in detoxification. One might also think that if it were indeed effective that there might be more anecdotal evidence as well as a possible black market in the drug (at least in the UK).

Comments by Andrew Byrne .. http://www.redfernclinic.com/

Washton AM, Resnick RB, Perzel JF, Garwood J, Gold MS, Pottash AC, Annitto WJ, Extein I, Kleber HD. Lofexidine, a clonidine analogue effective in opiate withdrawal. Lancet 1981 317;8227:991-993

Concord Seminar summary on Adult ADHD in those with substance use disorder.

Concord Dependency Seminar Tuesday 22nd July 2008

Adult ADHD & Substance Use Disorders � Dr Julian Trollor

Dr Julian Trollor is Senior Staff Specialist Neuropsychiatrist at the Neuropsychiatric Institute, Prince of Wales Hospital and Senior Research Fellow of the Brain Ageing Program at the University of New South Wales. He established a clinic for the assessment of adults with possible ADHD in 1995. This clinic now operates as a tertiary service, providing second opinions in difficult cases.

Dr Trollor began his presentation by recounting his own experience of filling out a pop-up box which once appeared unbidden on his computer screen. Dr Trollor (who does not have ADHD) was informed...."the responses you have provided indicate that your symptoms may be consistent with Adult ADD. It may be beneficial for you to talk with your healthcare professional about an evaluation.� The pop-up was sponsored by a manufacturer of a pharmaceutical for ADHD.

Dr Trollor pointed to the growing popular awareness of Adult ADHD (A-ADHD), with �self diagnosis� being common, shared controversy with its childhood counterpart, and community fears about treatment with a potential "drug of abuse".

ADHD is a "neurodevelopmental disorder of childhood onset characterised by impairments in cognitive function (inattentiveness), excessive motor behaviour (hyperactivity) and impaired behavioural regulation (impulsivity).� It is common, with high co-morbidity, and it is often overlooked, despite being relatively easily treated, with treatment improving outcomes.

Evidence for the validity of the entity A-ADHD has increased greatly in the last decade and is found in cross sectional, longitudinal and epidemiological studies, family & genetic studies, and neuro-psychological, -physiological, -endocrine and -anatomical studies.

Despite progress in understanding of A-ADHD, clinical diagnosis remains problematic: there is no single criterion marker; the core symptoms are dimensional (or spectrum) rather than categorical; co-morbidity can confound diagnosis; the requirement for retrospective childhood diagnosis may create difficulties; the key descriptors are ubiquitous; and the requirement for �significant impairment� is arbitrary. Diagnostic tests are often used but they lack specificity.

The DSM IV CRITERIA are listed in the appendix (see Redfern Clinic website). Briefly, the person must have (for the primarily inattentive type) six or more inattention symptoms as well as (for the combined type) six or more hyperactivity/impulsivity items for at least 6 months to a degree that is maladaptive. Some symptoms must be present before 7 years of age, impairment must be present in at least two settings, and symptoms do not occur exclusively during the course of a pervasive developmental disorder, psychotic disorder and (as always in DSM-IV) are not better accounted for by another mental disorder.

Symptoms can be grouped in four types:

1. attentional, with difficulty sustaining attention (during lectures, reading, in conversation, at work), easily distractability (eg by extraneous sounds, activity), day-dreaming, making careless mistakes - the primarily inattentional type is more common among women.
2. organisational, often losing things, forgetting day to day activities or appointments, having difficulty organising tasks, following verbal instructions - these may be more pronounced in unstructured settings, and therefore may become more problematic in adults, upon leaving a structured setting like school/college.
3. hyperactivity, being always �on the go� physically, being fidgety or restless, having difficulty relaxing, having racing thoughts or many ideas, taking on multiple tasks at once without finishing many.
4. impulsivity, talking excessively, making tactless comments, interrupting conversations, difficulty waiting turn, taking risks (eg driving, thrill seeking, financial risks), explosive temper, irritated easily by minor frustrations, quick mood changes.

Hyperactivity may be less marked in adults in whom the hyperactivity may be more a phenomenon of mental cluttering, akin to a sense of continuous "noise" - quite distinct from anxiety. A meta-analysis of follow-up studies of children with ADHD showed an age-dependent decline in ADHD symptoms: 65% experienced partial remission in adulthood, with full ADHD diagnosis persisting in approximately 15%. The severity of ADHD symptoms in childhood appears to predict persistence into adulthood.

A large cross-national survey estimated adult ADHD prevalence across ten countries to be 3.4% (range 1.2-7.3%); one US study estimated current prevalence of adult ADHD at 4.4%. As Dr Trollor pointed out, these estimates suggest that A-ADHD is one of the more common mental disorders.

ADHD is a condition with a high genetic loading - family studies suggest 80% of ADHD symptoms can be attributed to genetic factors - with genetic-environmental interactions also playing a role, especially disrupted attachment, early abuse, and chaotic environment. The candidate genes are those involved in motor activity and attentional processes, and include DAT gene (SLC6A3), COMT (Catechol-O-methyltransferase), DBH (Dopamine beta-hydroxylase) and dopamine receptors (especially DRD4), however no single gene accounts for more than 5% of the phenotypic variance of ADHD.

Adult ADHD has major consequences: adults with ADHD are less likely to be employed full-time and more likely to have unstable work records, have significantly lower household income, have fewer close friends, more difficulty sustaining relationships and higher likelihood of having contracted a sexually transmitted disease. They are more accident prone (more traffic violations, severe accidents, more likely to be �at fault�), and have higher medical costs.


In making a diagnosis, it is important to consider the motive/catalyst for presentation, whether owing to legal & forensic issues, a transition from a more to a less structured environment, or on cessation of substance use. Some adults come forward for assessment following diagnosis of their children. Self diagnosis is not a reliable indicator of the presence or absence of ADHD

The diagnostic pathway is to assess current symptom profile, severity and impact, to establish and corroborate childhood diagnosis (from self-report, parental and school reports, previous psychological or medical assessments) and to evaluate co-morbid (or diagnostically confounding) conditions - people with ADHD have increased risk of a diagnosis of antisocial personality disorder, of anxiety disorders, major depression and substance use disorders.

Bearing in mind the partial remission of ADHD in many or even most adults, it is important to consider the actual impact of symptoms on the patient's social, occupational, educational or family life as well as their current coping strategies. Many people cope well with or are untroubled by having features of ADHD and it is not uncommon for people with ADHD to be less likely to complain than their partners or family.

Establishing a retrospective childhood diagnosis is often a challenge, especially for people with major psychosocial problems including substance use disorder (SUD) who may have chaotic histories and be estranged from family. Where possible, informant interview can provide corroboration of the nature and extent of both current and past symptoms. Evidence can be gleaned from academic records, number and type of jobs, history of impulsive infringements, self esteem and interpersonal problems (resulting from impulsivity, poor anger control and organisational skills), and patterns of drug use which may suggest self-medication of symptoms. Sometimes there is a suggestive �paradoxical response� to street amphetamine - ie a calming effect rather than stimulation.

Further assessment may include the use of rating scales, and require physical examination, bloods testing including thyroid function, urine toxicology, EEG, CT/MRI of the brain (a history of head injury may be common in people ADHD owing to their accident proneness, but brain injury may also sometimes mimic ADHD symptoms), and neuropsychological examination including CPT. Not all of these will be required in every case.

Substance Use Disorders and A-ADHD

The epidemiological relationship between substance use disorders (SUD) and A-ADHD is bi-directional, with increased rates of SUD in ADHD clinic samples (for alcohol 17-45%, other drugs 9-30%) and of ADHD in SUD clinic samples (around 25%).

Relative risk of SUD in follow-up of ADHD cohorts is increased up to five-fold, with earlier and increased use of alcohol, tobacco and other substances in adolescents with ADHD compared to controls, and ADHD in childhood and adolescence a significant predictor for later substance use - the risk is greater if the individual has conduct disorder or mood disorder. The relationship of with childhood ADHD is strongest for tobacco smoking, and it is likely a sub-group of individuals with ADHD self-medicate with tobacco: nicotine has been successfully trialled as an intervention.

People who have both SUD and ADHD have poorer outcomes. However, people treated with stimulants in childhood and/or adolescence have an equivalent or lower incidence of SUD compared to those untreated, and the use of stimulant medication to treat people with ADHD does not increase the risk of developing substance use disorder.

It is preferable to perform diagnostic assessment during long-term abstinence (whereby opioid substitution treatment with abstinence from other problematic substance use can be considered abstinence) and, as with other co-morbidities, active SUD should be addressed prior to specific ADHD treatment. It should be borne in mind that ADHD medications have no demonstrated efficacy for the treatment of ADHD where there is co-morbid SUD, nor have studies been conducted of use of psychosocial interventions.

Dr Trollor recommended (and feedback is welcome about) the Draft Guidelines for the Assessment and Management of Attention Deficit Hyperactivity Disorder (National Health and Medical Research Council and the Royal Australasian College of Physicians) accessible at http://www.racp.edu.au/ ( follow link under �announcements�).

From these guidelines, the following are some key recommendations for best practice for assessment and diagnosis of ADHD in adults when co-morbid SUD is present:

People with personality disorder and/or substance abuse should be referred for evaluation of ADHD if they present with a significant level of hyperactivity / impulsivity accompanied by inattention.
Medication treatment for ADHD co-morbid with substance misuse should only be provided by a medical practitioner with expertise in both conditions.
ATX should be the first medication trialled if there is co-morbid substance abuse.

Management of A-ADHD

Dr Trollor's approach to management is to create a hierarchy for interventions, generally treating pressing co-morbid conditions first, as these may increase the expression of ADHD symptoms, and providing for further observation in cases where the diagnosis is uncertain.

Specific A-ADHD treatments include: education (through internet, books, support groups); drug therapies (methylphenidate 0.3-1.0mg/kd/day; dextroamphetamine 0.2-0.5mg/kg/day, desipramine, imipramine 25-100mg; and others including atomoxetine, buproprion, MAOI, lithium, venlafaxine, SSRI, CBZ, clonidine,); cognitive & other behavioural therapies to increase organisational skills, impulse control, and self monitoring.


Against a backdrop of a rapid rise in prescription rates, unease about use of stimulants arises from several considerations. With continuation of treatment from childhood there are potentially decades of exposure to stimulants. Should this be open-ended? What are the risks of psychological dependence, and harmful use/dependence given the high psychosocial and substance comorbidity in adults with ADHD?

Stimulants are effective in adults with ADHD although the number of studies is small. Available efficacy data for adults give response rates between 25 and 78 percent for methylphenidate (MPH), in a similar dose range as for children, and a modest literature suggest similar efficacy for dexamphetamine (DEX) - there is no direct evidence to support use of high or very high doses of MPH or DEX.

Current evidence suggests the use of stimulant medication to treat people, including children, with ADHD does not increase the risk of developing substance use disorder. However, there is evidence of diversion and misuse of prescription medications for ADHD among school students and college students, with between 16 and 29 percent of students on stimulant medication having been asked to give, sell or trade their medication at some time. While some individuals report using diverted stimulants to self-medicate for ADHD symptoms, others use them to enhance performance, or for their euphorogenic effects.

Dr Trollor advises stimulant treatment should be reserved for people with pervasive symptoms causing significant difficulty, and where clear goals can be identified, the patient is motivated to work on broad range of solutions and where adequate follow-up and monitoring is available.

Stimulant treatment is relatively contraindicated where ADHD symptoms are present but are not the primary problem, where the clinical diagnosis conflicts with patient �self-diagnosis�, where there is severe co-morbid psychosis or mood disorder, or continuing problematic substance use. One warning signal is where the patient has many past prescribers of stimulants.

Non-stimulants, long-acting stimulants or anti-depressants are preferred to short acting stimulants, which are strongly reinforcing drugs. Pharmacotherapy should be trialled for effectiveness on an individual basis and carefully monitored for benefits and adverse effects; a contract for stimulant treatment may include regular review (possibly including urine toxicology - a moot point at this seminar) and an ongoing goal of abstinence.

Atomoxetine is a predominantly presynaptic noradrenaline transporter inhibitor without euphorigenic and reinforcing properties, with several studies showing benefit in children and adults. There is also a small number of studies for buproprion (an indirect NA & DA agonist), likewise with a low �abuse potential�.

Stimulant Dose

There are no trials of �high� or �very high� stimulant doses in adults with ADHD, and low dosing appears to be appropriate for most individuals. Dr Trollor recommends cautious titration eg commencing at DEX 0.15mg/kg/day or MPH 0.3mg/kg/day and aiming for DEX < 0.5mg/kg/day or MPH <1.0mg/kg/day. For the stimulant-naive patient, Dr Trollor recommends commencing DEX 5mg mane & midi (or MPH 10mg mane & midi). Smaller doses may also be required if patient on other psychotropics or has comorbid anxiety or sleep disorder.

Animal models demonstrate a biphasic response to DEX: low doses (DEX < 1.0mg/kg) reduce, and higher doses DEX 1.0-5.0mg/kg increase, locomotor activity, which may correspond to a �high� in humans.

As stimulants lower the seizure threshold in animals, are associated with (transient) emergent �tics� in 10% of stimulant treated children, elevate pulse and blood pressure (low dose stimulants increase BP by an average of 3-5mmHg) low doses and close monitoring are indicated where there is co-morbid tic disorder, hypertension or seizure disorder. Although psycho-stimulants can induce paranoid delusions, auditory & visual hallucinations, this is mainly seen with intravenous use.

Inter-individual pharmacokinetic variability (especially for MPH, where peak serum levels vary up to five-fold) provides an argument for a trial of higher doses in some individuals with non response to low doses - monitoring stimulant levels may be helpful, as may a second opinion.

One difficulty is how to monitor response, whether subjectively or using self rating scales, observer rating scales, or neuropsychological/neurophysiological testing. Many people will feel better using low dose stimulants, regardless of whether they have ADHD or not. This conundrum was illustrated in a complex case study presented in the second half (see separate posting).

Some parting questions: how can such a prevalent condition, especially in children, be conceived of as a disorder? In an evolutionary sense, does ADHD confer an individual or collective biological advantage? In an anthropological sense, does it represent a failure of adaptation to modern life?

Summary by Richard Hallinan, based on Dr Trollor's presentation and powerpoint file.