SURVEY OF FORTY YEARS
Doctor Jean-Jacques Déglon Fondation Phénix Fouder
Treating heroin addicts with methadone substitution began in the USA in the sixties after the almost systematic failure of psychotherapies and short term weaning programmes. Prof. Vincent Dole, specialist in metabolic illnesses at Rockefeller University of New York, successfully tested the use of methadone, a substance synthesised by the Germans during the Second World War for morphine withdrawal.
The first clinical results are remarkable. Heroin addicts on methadone remain normal, without euphoria or withdrawal, abandon delinquency and are able to reintegrate themselves on a professional and personal level. For these reasons, methadone treatments multiplied, with more than 180’000 programmes all over the United States at the end of the eighties. However, there was great disappointment when the stability and quality of life of most patients were severely degraded by the weaning and stopping of methadone. Relapses were numerous. Without knowing the neurobiological bases of addictions, Mary-Jeanne Kreek (Prof. Dole’s collaborator) speculated on a probable dysfunction of the synthesis, liberation or degradation processes of one or many endorphins, or a defect of receptor response. She stressed the necessity of a correcting substance, methadone, administered on the long term (26, 27).
In Europe, medicalisation of addictions and substitution treatments were diabolised for a long time. They were understood as drug replacement prescriptions and were accompanied by addicted patients’ fears of social control and “chemical lobotomy”. The image of a synthesised heroin conveyed by the media gave the public a false idea of a pleasure drug, and generated diverse feelings aroused by access to that supposed pleasure. Doctors, long considered as accomplices of this so called pleasure, were then considered as “dealers in white blouses” and many were aggressively incarcerated, more particularly in Belgium.
In Geneva, following the publishing of an article on methadone treatments, opponents of the latter covered the walls of the city with posters proclaiming that “methadone is a narcotic that kills”, when in truth, methadone treatments diminish the number of overdoses. At the same time in the USA, posters showed a glowing young couple holding a child by the hand, flowering cherry trees in the background, with the slogan: “methadone harmonises life”.
Psychoanalytical experts, already hostile to medication that impairs speech, diabolised methadone to the authorities. The consequence of this moral context, generating aggressive feelings toward drug addicts, was that during a number of years, the only acceptable treatment programmes were, on the one hand, punishment through incarceration or re- education in residential therapeutic centres, on the other redemption through pain caused by fast weaning programmes. The more painful it was, the less relapses were meant to occur. This theory has however never been proven in practice.
Many factors have contributed in recent years to a radical change in mentalities, to progressive medicalisation of addictions and to the development of substitution treatment.
1. Novel cerebral investigation techniques and animal testing
First of all, novel cerebral investigation techniques and animal testing enabled the acquisition of new knowledge in the field of addiction neurobiology. This knowledge contradicted psychoanalytical theories of addiction and validated substitution treatment.
2. The AIDS epidemic
As long as drug addicts were self-destructive and a nuisance to no one but themselves, few people were interested in them. However, once it was established that a majority of drug addicts were infected by the HIV virus and were transmitting AIDS to the normal population, through prostitution among other things, interest increased in order to develop more efficient means of help.
3. Failure of short term drug weaning programmes and psychotherapies
The almost constant failure of short or average term abstinence programmes despite psychosocial support and patients often desperate efforts also favoured the development of the medicalisation of drug addictions. As a matter of fact, numerous international evaluations concerning the outcome of weaned heroin addicts observe that a large majority relapse in the short term. They also record an invalidating aggravation of their quality of life which often drives them to abuse, whether of alcohol, tranquilisers or cocaine (1 to 15).
Various psychotherapies without substitution medication revealed to be inefficient in maintaining abstinence. How can one explain these failures?
A state of deficiency is often observed following a fast weaning from heroin or methadone, more particularly after a long period of addiction (16 to 19). This state is characterised by deep anxiety, sleeping disorders, marked asthenia, fatigue, irritability, low self-esteem, relational difficulties, diminished cognitive functions (attention, concentration, memory), depressive tendencies, etc. This now well defined syndrome can last, in a more or less marked manner, from a few weeks to many months. It sometimes even seems irreversible, evoking a lasting malfunction of complex neurobiological regulation systems in the brain owing to opiate exposure that was either too long or too excessive. The psychological suffering that is brought on by the state of deficiency associated with the memory of pleasure states set off by the drug easily explains the frequent relapses of drug addicts. The relative inefficiency of antidepressants and neuroleptics in regulating this state of deficiency compared to the “miraculous” action of substitution medication, that often normalises observed disorders in a few hours, enforces the medical hypothesis of a disturbance in the functions of the opioid and dopaminergic systems (20, 21, 22, 55). Moerover, the state of deficiency reactivates reflexes conditioned by heroin, which often entails relapse (23 to 41). In 1979, Newman published a remarkable study (42) with 50 well stabilised patients using a double blind procedure (both therapists and patients were unaware). After 30 weeks of weaning, 90% of patients relapsed or presented a psychological decompensation. Only one patient (2%) was able to be weaned off of methadone without any problems. The results indicated a 98% failure to wean the subjects off of 1mg of methadone a day. This historical study consolidates the medical hypothesis that an important neurobiological basis facilitates and then maintains addiction (20, 36, 43, 44, 45).
Frequent relapse during or following weaning off of opiates and substitution products is also explained by the long term dysfunction of the stress system. All opioids are powerful antistress medicines. Mary Jeanne Kreek demonstrated that weaning off of opiates entailed an abnormal sensitivity to stress (43, 47, 48, 49). We have known for a long time that stress facilitates depression. The weaned drug addict, hypersensitive to stress, depressed, will be tempted to calm his psychological suffering by the use of drugs. However, a single dose of heroin or cocaine can immediately reactivate obsessive urges and entail a severe relapse - just as a recovered alcoholic who drinks even just the one glass of wine.
The brain remembers drugs. PET (positron emission tomography) scan techniques demonstrated that, when subjects are shown images which remind them of drugs, regions of the amygdalia, one of the memory centres are activated – causing the reactivation of violent urges for the drug.
BIOLOGICAL BASES OF METHADONE ACTION
An individually adapted dosage creates neither euphoria nor sedation in the heroin addict, owing to his acquired tolerance to opiates, to the slow absorption of the product taken orally, and to the fixation of 98% of the methadone on proteins when it first passes through the liver. The methadone is progressively liberated over a period of more than 24 hours (24, 50, 53, 54). Psychomotor tests destined for pilots were administered to a group of patients on methadone. The performance of the latter was better than that of normal subjects because they were less nervous. If the dosage is sufficient, a single daily dose enables the methadone to attach itself in a stable manner on the endorphin receptors. 5% to 10% of patients, genetically fast metabolisers, must take the methadone in two doses, one in the morning, and the other at night.
Clinicians have described the actions of methadone very well, especially during the first months of treatment. Its anti-stress, antidepressant and antipsychotic effects are remarkable, but how can they be explained?
Other than its stabilising effect on the opioid systems, methadone blocks the stress hormone and its unpleasant, anxiety causing consequences. It also acts on the neuromediator regulation mechanisms, such as serotonin and more particularly dopamine. A sufficient amount of these neuro-hormones is necessary in order to maintain a stable and acceptable sense of self. Most drugs used by addicts (cocaine, heroin, alcohol, haschish, nicotine, etc.) increase the dopamine concentration in certain parts of the brain, the pleasure circuit, by diverse action mechanisms (51). Opiates, by inhibiting the GABA system that brakes dopamine neurons, indirectly stimulate the latter which liberate more dopamine (blocking of the brake = acceleration).
To summarise, other than the fact that methadone greatly reduces heroin urges by attaching itself in a lasting way on morphine receptors, methadone also has a remarkable stabilising action on a psychiatric level without many secondary effects. This therapeutic aspect greatly dominates simple substitution.
Methadone taken even at a high dosage over a dozen years entails no medical complications, as opposed to many ordinary medications. With more than 3’000 studies published, it is one of the most researched molecules in the world.
SUCCESS OF SUBSTITUTION PROGRAMMES
Pharmacotherapy potentialises efficient therapeutic action. Methadone restores a state of normality and thereby facilitates a lasting abstinence by favouring a good psychosocial equilibrium. It also favours a smooth course and success of psychotherapy.
The stability that these substitution medications engender also encourages action from the social workers and reestablishment of healthy affective relationships with close ones.
Results of numerous methadone programme evaluations (implying the joint action of substitution medication and psychosocial support) are impressive concerning the decrease in delinquency and almost total suppression of heroin use when the methadone dosage is individually adapted to needs. The degree of psychopathology of drug addicts is the principal factor negatively influencing the quality of results.
Numerous international evaluations have highlighted the importance of an adequate dosage of methadone in order to obtain and maintain good results. But which methadone dosage should one prescribe? One shouldn’t speak in terms of low or high dosage, but in terms of individualised adequate dosage, based on clinical symptoms and laboratory results. How much does one give? The answer is “enough”. But how much is enough? In 1992, Payte and Khuri gave the official answer: “enough is the necessary quantity in order to obtain the desired therapeutic response, during the desired lapse of time, with a sufficient margin of security and efficiency”.
The absolute indication for increasing a patient’s methadone dosage is continued use of illicit opiates. An adequate amount of methadone in the blood (methadone levels in the blood) helps determine the right methadone dose. Over 24 hours, the methadone dosage in the blood must not be too high, for example over 800 nanogrammes per millilitre so as not to cause signs and symptoms of intoxication. The dosage must not be too low either, for example beneath 400 nanogrammes, in order to avoid subjective symptoms of withdrawal and, more importantly, objective signs of withdrawal, such as below 200 nanogrammes per millilitre.
Heroin quickly brings on a state of euphoria followed 2 to 3 hours later by a state of withdrawal that demands new intakes. Thus, during 24 hours, one witnesses many moments of euphoria, followed by a brief state of normality preceding the withdrawal state.
Correctly dosed methadone must not entail a state of euphoria during the absorption peak 4 to 5 hours later, but must maintain a normal state over a period of more than 24 hours. That is the adequate dosage. An insufficient, inadequate dosage leaves the patient in a state of withdrawal after a few hours.
Over the years, recording better results in our patients through the correct dosage of methadone, we progressively adapted the doses. In 1992, the mean dosage of our patients was of 57mg, in 1996 of 66mg, in 1998 of 80mg and in 2003 of 92mg. Today, the mean dosage of our patients is 100mg.
The most remarkable result of methadone treatment programmes is the strong decrease in heroin usage. In 1992, despite the mean dosage of methadone, we witnessed a decrease of 98,6% of heroin use per month compared to the month preceding the programme. These last years, this decrease stabilised at 99%. We recorded a reduction of heroin usage according to the methadone dosage. In 1992, with a mean dosage of 57mg, 33% of our patients used heroin during the month preceding the evaluation. This proportion progressively diminished to 17% in 2003 with a mean dosage of 92mg. This decrease is particularly marked in patients taking a high dosage (higher than 140mg). In this group of patients, we observed only 0.2 heroin intakes the last month compared with 1.6 for patients with a methadone dosage beneath 140mg.
The layman’s notion that drug addicts on methadone are “high” just as with heroin is false. In fact, as mentioned earlier, psychomotor tests showed normal abilities. During our evaluation in 2003, we asked 368 patients with a correct methadone dosage to grade from 0 to 100 the quality of their psychomotor reflexes, their ability to drive and their degree of concentration and attention. 72% of them indicated that their capabilities were 100%. Only 4% graded below 70%.
On the other hand, we recorded a decrease in libido proportional to methadone dosage. We calculated a libido indicator taking into account patients’ point of view and the frequency of their sexual activity. Libido decreases according to dosage. Hormonal doses showed a decrease of testosterone, be it free or total. This decrease is explained by an insufficient amount of the hypophysiairy hormone LH in a majority of patients with high levels of methadone. 73% of subjects receiving more than 120mg of methadone had LH levels inferior to the norm of 3 units per litre. Taking into account the low testosterone and reduced levels of LH without prolactine increase, leads one to think of the inhibiting action of methadone on the hypothalamo-hypophysiary system, as occurs with all other opiates.
Another problem regarding high doses of methadone is the cardiac rhythm disorder, more particularly the lengthening of the QT space that can entail death by torsade de pointe. Electrocardiograms administered to all our patients receiving a dosage above 150mg revealed that the QT space was proportional to the dosage. In total, 38% of these patients had a normal QT, 53% a slightly lengthened QT and only 9% a QT lengthened by more than 10%. Only one serious lengthening of the QT obliged us to replace methadone by delayed morphine.
Another spectacular result of methadone programmes is the stunning decrease in delinquency. We compared the number of days our patients spent in prison according to the years of heroin addiction before treatment with the number of days in prison during the 12 months preceding the evaluation. In 1992, we observed a decrease of 92% of days of imprisonment, and progressively, with a better methadone dosage, obtained a decrease of 96% in 2003.
Methadone treatment also greatly reduces high risk behaviour, AIDS or hepatitis contamination and number of deaths.
Concerning HIV seroconversion levels, we observed 6 cases of HIV negative patients who became HIV positive during the programme - this over a period of eleven years, from 1992 to 2003. 5 of the cases were related to cocaine use. The obsessive urges for this drug favour compulsive and dangerous behaviours that neither intelligence nor preventive information suffices to control. We recorded an annual seroconversion level of 0.5 cases. Considering an annual mean of 445 patients, one can say that the proportion of seroconversion per patient and per year is of 0.1%.
The proportion of deaths of our patients on methadone is also very low. We noted an annual proportion of 0.7% for a mean of 550 patients these last years and a present average of 37 years of age. This average of 4 deaths per year is rather low when one takes into consideration the important psychiatric disorders of this population and the importance of their infectious disease antecedents. Indeed, we observe strong psychiatric comorbidity among patients in methadone treatment. This confirms the fact that many young drug addicts develop substance abuse searching for “something better” concerning their anxiety, depression or psychosis.
Maron and Kreek undertook a thorough study of 53 men and 50 women in methadone treatment. They recorded that 72% of them suffered psychological disorders before the first use of drugs. They also observed a decrease of 50% in those disorders during methadone treatment. 51% of patients had depressive disorders, 45% phobic disorders, 37% antisocial personality disorders, 32% anxiety disorders, 24% alcoholism, 20% obsessive-compulsive disorders and 19% somatic disorders.
In 2003, in order to better comprehend the success or failure factors of methadone treatment, we asked 370 patients 430 questions. Computerised analyses of the answers allowed us to conclude that the degree of psychopathology is the most important factor, the most sensitive factor and the one that best correlates in prediction of the quality of results of the treatment and future prognostic.
Taking into account approximately 30 indicators of a psychological problem, we defined a psychopathology indicator with a scale of 0 to 200. 14% of patients with less than 50 points represented group A, the most normal. 54% of patients with 51 to 99 points represented group B of average psychopathology. 32% of patients with more than 100 points represented groupe C, with high psychopathology.
We recorded that overdoses before treatment were proportional to the degree of psychopathology, as was heroin use before treatment and alcohol problems. We also observed cocaine use frequency 30 days prior proportional to the psychopathology indicator, as well as the proportion of patients having a full time job. Subjects benefiting from the invalidity insurance were 9 times more numerous in group C than in group A.
ADVANTAGES OF SUBSTITUTION TREATMENTS FOR THE COMMUNITY
We have summarised the interest of substitution treatment for patients, but the community also benefits from it: the cost-efficiency relationship of methadone treatments is remarkable.
In terms of public health, the possibility of a large medical prescription of methadone for heroin addicts greatly diminishes overdoses, delinquency, medical complications, AIDS risks and the costs of necessary social aid.
If the offer of treatment is sufficient, heroin traffic breaks down and decreases the number of new addicts. This situation has been observed in Geneva and elsewhere.
Government has a great financial interest in supporting and developing substitution programmes since the latter can also considerably lower the exorbitant cost linked to drugs (medical, police, judicial, social). Many economical studies have shown that for 1 euro invested, the resulting economy was approximately 10 euros.
Even if psychosocial support, though more costly, remains very useful or even necessary, countries with lesser resources can already expect fast success in the domain of heroin addiction by organising simple yet rigorous programmes of daily prescriptions for drug addicts, during the necessary amount of time. Part of the economies – often quite rapidly made - can later be paid back to therapeutic programmes in order to enable them to reinforce their psychosocial help.
CAN ONE SUCCESSFULLY END A SUBSTITUTION TREATMENT?
All evaluations unfortunately confirm that only a minority of drug addicts can be successfully weaned off their substitution medication in the long term - more particularly those maintaining drug abstinence for more than a year, without psychiatric comorbidity and with minor addiction precedents. A maximal reduction of 3% of the methadone dosage per week is recommended.
Today, new genetic hypotheses are suggested. Some subjects could suffer genetic defaults from birth. Particularities involving certain genes would entail the dysfunction of certain chemical neuromediators of the brain or their receptors (50, 52). These subjects would then also be particularly sensitive to the effect of drugs and more prone to develop an addiction. Adolescents with psychiatric disorders, such as borderline personality disorder, depression, psychotic symptoms, obsessive-compulsive disorders or hyperactivity with attention and concentration deficit, feel better on a psychological level, at least at first, with heroin, and are then tempted to perpetuate that appeasement.
The near miraculous psychological change described by many of our patients with psychological difficulties, when they first use heroin, strongly contrasts with the usual indifference of patients having received morphine in hospital and who never felt the need to continue once outside. For the former, it is as though all their lives they had seen only in black and white and that, with opiates, they could at last see in colour. Their determination to maintain, no matter the cost, this better quality of life is understandable.
Methadone treatment enables this better equilibrium in the long term. Below a certain dosage however, it is normal that underlying psychological problems reappear, as do the tremblings of an epileptic who greatly reduces the dosage of his medication.
For the last 40 years substitution treatments have proven their efficiency. They have enabled hundreds of thousand of drug addicts in the world to avoid psychological and physical decline as well as fatal outcomes by stabilising them in a lasting fashion and returning to them a sometimes exceptional quality of life. On the other hand, even a very progressive stop in the substitution treatment often entails a loss of this quality of life, psychiatric problems and relapse into alcohol or drugs - this particularly in patients with psychological disorders underlying the addiction. For them, the drug must be understood as an attempt to self-stabilise psychological suffering that, to the professional, seems more and more related to genetical neurobiological dysfunctions. The substitution medication then acts as a corrector of the biological defect that corresponds to a chronic illness. For these patients, substitution treatment must be considered as a medical treatment that rectifies a natural imbalance and that must be maintained over an unlimited amount of time as, for example, must insulin for a diabetic or treatment for an epileptic.
It is therefore of the utmost importance to carry out a complete evaluation in order to be able to identify medical, psychological, affective, social, familial and professional problems involved as pre-existing or secondary factors of the addiction and thus to offer specific therapeutic responses. This evaluation also enables an eventual weaning.
To conclude, the most important thing is to enable each heroin addict to have immediate access to a form of therapy that suits him - or to many if necessary - so that he may find a good medical and psychosocial equilibrium as soon as possible and maintain that quality of life in the long term. Substitution programmes have proven these last forty years, to be the most efficient answer to these expectations.
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