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  EUROPAD journal December 2006: poor articles, poor editing, best ignored

Posted: May 16, 2007 14:09

EUROPAD journal December 2006

Heroin Addiction and Related Clinical Problems. December 2006. Editor Icro Maremmani, University of Pisa.

This journal�s advisory panel boasts a bevy of senior members of the addiction specialty world-wide. Yet the quality of its articles in the December edition is well below the standard we find in other dependency journals. The quality of some items is almost embarrassing in that they lack basic aims, a coherent structure and execution.

The �diatribe� of Gossop (Methadone - is it enough?) is most disappointing, coming from someone so eminent and experienced (see below for my personal vivisection). His subject could be interesting, but he develops the sentiments as if methadone was to be seen in total isolation rather than as just one tool in the dependency repertoire, also forgetting that methadone is one of the commonest pathways towards long-term abstinence. He does not even mention buprenorphine once in the entire long article! It would be like saying �Penicillin is not perfect!� Well, of course it isn�t!

Editor Maremmani�s opening editorial is confusing and poorly argued. He writes about �Discarding the Label "Substitution Treatment" in Favour of "Behaviour-Normalization Treatment". He states (incorrectly): "We remember that Dr. Dole never spoke about �substitution treatment� and that, in his experience, methadone was a behaviour-normalizing drug which would re-balance the endogenous opioid system persistently damaged by toxic narcotics such as heroin. This happens only when methadone is administered at adequate dosages and as a maintenance regimen."

This is putting words in the master�s mouth on several counts. I knew Vincent Dole quite well. Maremmani also misquotes Vincent Dole on the terms 'replacement' or 'substitution' treatment. I recall that Vince Dole did not particularly care what MMT was called, as long as it was given in sufficient doses with appropriate supports and safeguards. It would seem that Maremmani himself does not read his own journal since Dr Dole himself is quoted in this very issue (p13) "From this perspective methadone maintenance is replacement treatment, compensating for impairment in function of natural opiate-like substances" [Dole VP. Methadone maintenance: Optimizing dosage by estimating plasma level. J Addict Dis 1994 12: 1-4]. Maremmani also published an article entitled: �Opioid Substitution with Methadone ��. Also, contrary to his statement above, heroin is not necessarily a �toxic narcotic�, just as methadone is not always a 'behaviour normalizing' drug. The opposite can also be true since heroin may be therapeutic while methadone may be abused.

So why would Icro Maremmani write such confusing, unreferenced material? Like Gossop in the same issue, he writes about methadone as if buprenorphine, long acting morphine, prescribed heroin and dihydrocodeine did not exist! Do they have a serious "agenda" or could they just possibly be operating on auto-pilot, I wonder?

Editor Maremmani certainly works quickly. He �received and accepted� 4 of the five articles on the same day that they were received. Only one item (Reisinger on injection of buprenorphine) took him 2 months to decide on. Perhaps he ought to have spent more time editing and less time �opinionating�. The item by Schmittner and Krantz on cardiac effects in methadone patients is also flawed and unbalanced in my view.

Reisinger grapples valiantly with the difficult subject of buprenorphine injecting. As there is almost no controlled research on the subject, his findings and conclusions are as valid as any.

�QTc Prolongation in Methadone Maintenance: Fact and Fiction.� Schmittner J, Krantz MJ.

This opens with a statement that methadone was: �until recently, was viewed as a medication without cardiac properties.� Krantz should know this to be untrue since he has previously cited a study from the 1970s (Lipski) which had a major incidental finding that a high proportion of (unstable) methadone patients had QT changes. It is hard to know why this subject is even being discussed at this level when there is still not one series in the world literature of symptomatic, documented cases from the large ranks of �normal� MMT subjects. In fact, I have still not read of one single convincing case, although it is quite certain that �torsade de pointes� must occur at some rate in 'normally' treated dependency patients just as it can occur in those on other medication or indeed in those not taking any drugs, due to a familial predisposition.

In recent articles and talks, Krantz and colleagues have been saying that (1) we need to be really careful about providing �high� (>120mg) doses of methadone (2) there is a therapeutic 'paradox' that higher and (therefore) �more dangerous� doses of methadone are also proven to be associated with lower rates of illicit drug use and (3) alternatives such as detoxification or transfer to buprenorphine should be considered in place of higher doses in certain (unspecified) cases. This latter suggestion is more than revealing.

In my view these three pieces of advice are unhelpful and inappropriate. They could even be dangerous. Do these authors believe that clinicians were not 'careful' before this issue was raised by them? As with other medication, doctors should only prescribe when non-drug treatments have proven ineffective and then, we should always employ the lowest effective dose of the most appropriate drug. If we followed Krantz' (unspecified but guarded) advice, our patients may actually stand to develop MORE torsade de pointes through increased illicit drug use. His original report involved a high proportion of pain management cases and the mean dose was 397mg daily, while 15 out of 17 (none of whom died) had other risk factors for QT effects and tachycardia. If any of the drug abuse patients were using cocaine then the appropriate response may be higher doses of methadone which are proven to be protective in this regard (see Borg, Kreek et al).

The present article tells us blandly that: �The likely mechanism of arrhythmia development is blockade of the human cardiac ether-a-go-go-related gene (HERG) delayed-rectifier potassium current.� Who are we to argue, yet this is not very helpful for a �side effect� which is still not established, and if it were is certainly extremely uncommon. Certain dangerous situations such as overdose, needle sharing and 'dirty injections' are every day occurrences in our patient group and these can be reduced dramatically by simply optimising doses of methadone (in England the average was reported by Strang to be 37mg daily!! No wonder they think MMT does not 'work'!).

Krantz has also stated again that his revelations will be of even more importance with the 'worldwide expansion' and community use of methadone treatment in the future. What does he mean? That we need to slow down the opening of methadone clinics in China or South America because of his important work? He has yet to publish an estimated prevalence of torsades in regular MMT subjects treated under existing guidelines (it would be difficult, since there appear to be no series of such cases). From reports to FDA cited by Peles and Kreek the prevalence of such complications may be one in ten million doses. This makes aspirin look mighty dangerous!

Krantz has stopped writing about 'torsades' (which may or may not occur as a result of 'normal' dependency treatment) and now just addresses �QT prolongation� (which does occur as a result of methadone doses, but is usually asymptomatic). �Prolongation� is mentioned 28 times in the article, �torsade� only twice (excluding references). In his original article of 2002 �torsade� was mentioned 27 times while prolongation only thrice. The point is that QT prolongation is usually asymptomatic condition while torsades is an arrhythmia which is quite often fatal. It seems that most of the small number of cases are from tertiary referral centres in patients with complex medical illness as well as high doses of methadone in combination with other drugs, legal and illegal.

Gossop M. Methadone - is it enough? Heroin Addiction and Related Clinical Problems. December 2006.

This article is one of the least edifying pieces of medical writing I have read. It is still a mystery to me why so many intelligent colleagues in England keep going around saying the same old things, viz: that methadone maintenance treatment (MMT) is not perfect and so there must be a better way, or words to that effect. Strang wrote that methadone may yet have a �sting in the tail�. Well of course MMT is not perfect, and that is why we need alternatives, such as the new heroin injecting trial in England (not mentioned in this article for unknown reasons; nor is the fact that it has taken British colleagues 27 years since Hartnoll's last published work on the subject).

Appropriate medical treatment of addiction involves some patients taking methadone for certain periods. Gossop knows that. We know that. It also involves some patients taking maintenance buprenorphine, others having short detox episodes, others still longer term rehabs, etc, etc. Gossop�s tedious discussion over reduction versus maintenance 'programmes' is awkward, unproductive and academic. Despite some doubtless well-meaning intentions, such distinctions are almost always blurred and ill-defined, thus making them irrelevant clinically.

So it is a mystery why anyone would waste breath, time and effort discussing shortcomings of the very modality which has been so well researched for 40 years. Especially so when many of these shortcomings refer to the English experience reported in NTORS (National Treatment Outcomes Research Study). This latter �study� is almost meaningless scientifically, yet it parallels good research done by John Strang and colleagues that the quality of MMT in England is so poor that mean doses have been reportedly as low as 37mg daily.

Apart from poor editing [eg. "In some respects, it is encouraging that only a minority of patients showed achieved such poor outcomes." p59], he studiously avoids discussion of the important and even crucial issue of dose supervision. And they also bring up the �canard� that there is "still controversy" over dose levels! Dose guidelines in almost every country now agree (most patients need 60-120mg daily with a small proportion needing more or less for metabolic reasons). Despite many differences of opinion of details of treatment, dose levels is one area in which there is very little controversy left amongst addiction experts. One might equally say vaccinations and insulin treatments are 'controversial' which they very well may be in minority quarters.

Almost every doctor who has every prescribed methadone for any length of time has had certain patients taking over 100mg and who are demonstrably doing well and who fared less well on lower doses. Vincent Dole's first report of 25 patients had several taking 180mg daily and an AVERGE dose of 106mg daily. So why would Gossop regurgitate irrelevant and confusing information? While it is true that most controlled research has involved patients taking lower doses than 120mg, it is also true that most patients in US clinics where most such research was performed were taking less than 120mg, hence the circular argument on research relating to doses. In fact there is now quite a substantial literature demonstrating that higher doses benefit a proportion of people who otherwise on these apparent recommendations here would count as failures. Hence it is inescapable that from what is written here, if taken seriously by our newer colleagues in Eastern Europe who are targeted by this Journal, could cause sub-optimal treatment to be given. If they looked at the article in an even slightly less positive light, they may well decide not to prescribe methadone at all. It is hard to imagine any other area of medical practice in which we would see 75% response rate to a single drug in a �negative� light, as Gossop appears to. For rheumatoid arthritis, diabetes, depression, hypertension, etc, this response rate would be impressive indeed.

How could one possibly write a serious article about the limitations of methadone without even mentioning buprenorphine? My guesstimate is that the introduction of buprenorphine into normal dependency practice over 7 years has improved outcomes in my own practice from about 75% (much the same as Gossop�s quoted figures) to over 90% on normal outcome measures. We may learn more from up-coming Scandinavian controlled research on the subject.

Few of these articles would have been accepted by serious medical journals in my view.

I recommend avoiding this journal in favour of the mainstream literature. Readers may be surprised at me recommending Addiction, published by the Society for the Study of Addiction in England. To receive this journal at �mates rates� one need only join the society for 75 English pounds. This includes 12 Addiction issues plus supplements and Addiction Biology plus an internet subscription and access to a web based notice board and chat line (which sadly is hardly used by anyone, it seems).

Comments by Andrew Byrne ..



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