PRELIMINARY FAVORABLE RESULTS OF SUPERVISED HEROIN TREATMENT REPORTED IN LAY PRESS IN UK:

The Independent headline says it all: "Britain's first drug 'shooting galleries' hailed a success," and is echoed by the accompanying editorial comment under the title, "Leading article: 'Shooting galleries' work" - both published Nov. 20. The positive outcomes were with regard to the individuals who received IV heroin; two other groups, receiving oral and IV methadone, respectively, are not mentioned in the Independent story.

The one disappointing note is the final line in the editorial: "The next stage is to wean addicts off their drugs. That has yet to be tested." To the extent it is implied that total abstinence from heroin and all other medication is the goal, one can readily predict the results of such a "test" on the basis of many decades of experience. Probably this is just an incorrect understanding of the protocol and future plans for extension.

More specifics as to the trial procedures and outcomes will hopefully be forthcoming before long. Meanwhile, the trial itself is a tribute to the investigators, the government authorities that permitted it, and of course the patients. URL for the article and the editorial:
Article

Editorial

CARDIAC ARRHYTHMIA ISSUES POSSIBLY RELATED TO METHADONE TREATMENT

Comments from Dr. Byrne, an Australian colleague based on journal article below:
Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Dear Colleagues,

Krantz and colleagues’ latest foray into the purported cardiac consequences of methadone treatment has mixed messages. Their survey of methadone clinics finds a majority of clinicians have not heard of what might be termed “Krantz syndrome”. The paper states that “only 41% (95% CI, 37- 45) were aware of methadone’s QT-prolonging properties.” Yet further: “emerging evidence suggests [methadone] may … prolong the QT interval.” But then again more forcefully: “methadone is now categorized as a medication definitively linked with torsade de pointes …”. Are they having a bet both ways on causality? The evidence on this is conflicting as Martell apparently found a significant association between dose and QT interval where Peles, Kreek et al found no such correlation, including blood levels, in a large study from Israel . Krantz and colleagues fail to cite the Peles study although it was available on the net in early December 2006.

Most reports of QT prolongation in methadone patients, eg. Pearson; Walker; Krantz; Ehret, involve (1) ‘mega-doses’ (>300mg daily), (2) other cardio-toxic drugs, (3) abnormal metabolic states (such as hypokaloaemia) and/or (4) heart disease. Only a small minority of reported cases could be termed ‘regular’ methadone clinic patients from my reading. And yet it is these very patients who Krantz gives advice to avoid methadone if possible and when it is used to avoid ‘high’ doses.

To most dependency researchers, ‘high dose’ means more than 100mg daily. For discussion of QT problems ‘high dose’ would appear to mean more than 300mg daily, with the highest reports nearly 2000mg daily! The mean daily dose in Krantz’ original study was 397mg; Pearson 410mg; Walker >600mg. These are not the sort of doses dependency doctors are usually familiar with.

Since so many of the cases quoted by Krantz refer to pain management, it is surprising that this survey only involved addiction clinics.

This whole exercise seems to ignore the consequences of NOT giving methadone - which about 1 million people world receive today, and for most there is no alternative, at least none that would be affordable. Even if methadone were a cause of cardiac complications, Krantz gives us no clear strategy to prevent them, short of forgoing treatment with methadone altogether or giving lower (and therefore sometimes inadequate) doses. Hence, apart from raising anxiety levels, it is hard to see how Krantz’s long campaign on this subject has contributed to the field. It is likely that his perspective would be broadened if he had collaborated more closely with dependency specialists. The advice he is giving to the field is contrary to almost all established guidelines which stress adequate doses of methadone to reduce harmful injecting behaviour.

In Lancet Krantz quotes a study of methadone related deaths to justify focusing on this issue. Yet this study finds that only 4% of the deaths occurred in patients in addiction treatment programs (Ballesteros 2003), and there was absolutely nothing to suggest that cardiac effects played any role whatsoever.

It is still likely in my view that the reduced level of cocaine and heroin use with higher methadone doses shown by Dr Lisa Borg some years ago should actually protect against cardiac arrhythmias - to say nothing of the many other life-threatening concomitants of illicit heroin use. Others have written about the cardio-protective effect of methadone in ischaemic heart disease (Marmor).

Adding to the confusion, while stating that doctors should take account of this syndrome when prescribing methadone, Krantz still does not recommend routine ECG before starting methadone treatment. Ellen Pearson agrees with this assessment in her paper with Woosley, stating further that limiting the dose of methadone is unlikely to completely avoid cardiac complications. As far as I am aware nobody has yet reported a series of cases of cardiac arrhythmia in ‘normal’ methadone patients, so how can this be a public health issue?

Although Pearson’s 59 FDA reports did not specify whether methadone was prescribed as part of an addiction program or otherwise, one may deduce that no more than 14 of the cases would likely have been ‘normal’ clinic patients and only one death occurred in this group in a patient reportedly taking 29mg daily (I have never been in a clinic which could measure 29mg, raising the possibility that this is a mistake/typo etc). Even as Krantz states that the FDA reports are an underestimate of the prevalence of this complication, there are still only the most sparse number of cases considering well over a million Americans have been on the treatment over the years (~240,000 currently). I also note that of 5 deaths in Pearson’s excellent report, only one of them had torsades, the fatal arrhythmia associated with QT changes, raising the possibility that there was only one cardiac death out of 59 cases.

In my view it is likely that the 59% of clinic doctors who had not heard of QT changes were possibly giving better quality treatment to their patients than the ‘enlightened’ minority who only reported a handful of cases to the FDA over a 30 year period.

Comments by Andrew Byrne ..

I note that of 7 web citations in this paper, 6 did not link to the correct (or indeed any) site. This may be a common problem with changes to web addresses yet it must also be a weakness of a scientific paper when peer-reviewed published citations are always to be preferred where possible in my view.


Krantz MJ, Rowan SB, Schmittner J, Bucher Bartelson B. Physician Awareness of the Cardiac Effects of Methadone: Results of a National Survey. Journal of Addictive Diseases 2007 26;4:79-85

Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Saf. 2005 14;11:747-753

Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005;95:915-8

Peles E, Bodner G, Kreek MJ, Rados V, Adelson M. Corrected-QT intervals as related to methadone dose and serum level in methadone maintenance treatment (MMT) patients - a cross-sectional study. Addiction 2007 102;2:289-300

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in Deaths Due to Methadone in North Carolina. JAMA 2003 290:40

Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368:556-557

Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366

Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, D. Robertson AD, Mehler PS. Torsade de Pointes Associated with Very-High-Dose Methadone. Ann Intern Med. (2002) 137:501-504

Walker PW, Klein D, Kasze L. High dose methadone and ventricular arrhythimias: a report of three cases. Pain 2003 103:321-4

Ehret GB, Voide C, Gex-Fabry M, Chabert J et al. Drug-Induced Long QT Syndrome in Injection Drug Users Receiving Methadone High Frequency in Hospitalized Patients and Risk Factors. Arch Intern Med 2006 166:1280-1287

Marmor M, Penn A, Widmer K, Levin R, Maslansky R. Coronary artery disease and opioid use. Am J Cardiol. 2004;93:1295-1297

METHADONE ISSUE NEEDS REAL UNDERSTANDING:

Below is a good comprehensive Letter to the Editor responding to atrocious comments from a judge and prosecutor in New Hampshire.

Nov. 10 - To the Editor:
I am writing to express an alternative opinion to those expressed by both Judge Sawako Gardner and county jail superintendent Al Wright in the Nov. 9 Herald article by Elizabeth Dinan about the request of a "jail-bound woman" to continue her treatment for opiate dependence at an area methadone clinic.

Firstly, I would like to extend my thanks to both Gardner and Wright for their service to the community. As a fellow community member, however, I would like to offer some more accurate information about both addiction and the medically-based treatment of addiction.

As I am sure both Mr. Wright and Judge Gardner are aware, New Hampshire has a significant and rapidly increasing rate of opiate dependence. The cost to the community of any disease is high, but can be ameliorated with accurate information and appropriate services.

As scientific advances have been made regarding addiction, the stigma under which persons with addictions live has begun to lift. However, many misunderstandings still abound. Though there are other ways to treat opiate dependency, methadone therapy has been proven to be one of the most efficacious. Methadone treatment for opiate dependence has been used since the 1940s. Like the disease of addiction, methadone treatment has been stigmatized and misunderstood for decades. In conjunction with a daily dose of medication, methadone therapy, by law, includes participation in counseling for all patients. The medication treats the damage inflicted upon the brain by the abuse of opiates and keeps the patient stable (i.e., free of acute withdrawal symptoms and cravings) while, in counseling, they make the changes in their lives they need to make to live a life free of illicit use.
Because the abuse of opiates has such a profound impact on the brain, recovery is a long process. It is possible that the brains and bodies some opiate dependent persons will repair themselves in time. However, there is a percentage of patients who will need to be maintained on opiate replacement therapy for long periods of time - sometimes for life. When a patient decides to taper from his or her stable methadone dosage, it is done slowly and in conjunction with a physician and his or her counselor to lessen the chances of relapse and the return of withdrawal symptoms. Treatment is individualized and, therefore, it is both impossible and unfair to the patient to determine a length of time in treatment without accounting for individual situations and needs. Though both Judge Gardner and Mr. Wright posit that "long-term use is not recommended," studies of the efficacy of methadone treatment have proven the opposite (see Gerstein, et al. Evaluating Recovery Services: The California Drug and Alcohol Treatment Assessment (CALDATA): General Report. 1994; National Institute of Health (NIH). Effective Medical Treatment of Opiate Addiction. 1997).

Methadone treatment, therefore, is not a "legal addiction," but a replacement therapy for persons with the disease of addiction that allows them to live healthy, drug-free lives. Much like people with diabetes use insulin, methadone is used to make up deficits in the body's physiology. Though I understand that providing treatment to inmates is a "burden" when viewed in a certain light, I believe it is our duty as a community to increase our understanding of the problems we are facing - and viable solutions to those problems. Though the immediate cost of facilitating one inmate's continuation in methadone treatment might seem high, supporting treatment for addiction has been proven to lessen the costs to the community in the long run.

Lisa Feldman
Portsmouth

THE BUPRENORPHINE PROMISE:

The Fall, 2007, issue of NYU Physician contains an article concerning research on buprenorphine treatment of addiction that is being carried out by NYU researchers and clinicians. It’s great that the application of buprenorphine continues to be studied. On the other hand, the direct and indirect references to methadone maintenance, more than 40 years after its efficacy was first reported, are terribly distressing. Thus, buprenorphine is said to offer the "unprecedented . . . opportunity [of] readily available [addiction] treatment, in private, with dignity." In other words, the estimated 250,000 hapless patients receiving methadone in the US today are considered (with considerable justification!) to be denied private, dignified care, and for many tens of thousands of others methadone is not available at all - readily or otherwise.

In addition to pursuing the "opportunity" that buprenorphine offers, colleagues at NYU and elsewhere should seek energetically to counter the stigma associated with methadone treatment and what the article states are its "many restrictions that, in a way ... [have] the same panache as being sent to jail." What a horrendous statement - all the more so because it is largely true!

It does not seem overly pessimistic to predict that if the attitudes, regulations and policies governing methadone are not changed, the promise of buprenorphine will never be fulfilled.

SOBRIETY:

An article recently appeared entitled, “What is recovery? A working definition from the Betty Ford Institute” (J Subst Ab Treat 2007 33:221-228).On the one hand, it is encouraging to read that the panel convened by the Institute believes “sobriety” does not preclude individuals “maintained by a medication...“. On the other hand, the definition demands abstinence from alcohol (though not tobacco!); one must wonder why this is considered a sine qua non for the former heroin user, whether or not receiving any prescribed medication, to claim sobriety. Also, the panel considers “citizenship” to be essential, since it is deemed to “capture important traditional recovery elements such as ‘giving back’.” Why should a history of drug or alcohol dependence be the basis for a greater or lesser obligation to “give back” to the community – or to anyone else?

GUIDELINES VS. RECOMMENDATONS: A DISTINCTION WORTH NOTING

A colleague in Germany, Dr. Albrecht Ulmer, called attention to the difference between “guidelines” and “recommendations.”

According to Webster’s Unabridged Dictionary:
Guideline: “a standard or principle by which to make a judgment or determine a policy”
Recommendation: “advice; counsel”

According to the New Shorter (4,000 pages!) Oxford Dictionary:
Guidelines: “directing or standardizing principle”
Recommendation: “counsel or advice”

In German the distinction is even clearer Cassell’s German-English Dictionary):
Richtlinie: “direction; rule; instruction”
Empfehlung: “recommendation; advice”

As someone generally extremely loose about semantic nuances, who has always viewed these two words as essentially synonymous, it seems the distinction noted by Dr. Ulmer is an important one, that should be kept in mind as one reads and/or promulgates opinions in the complex medical field of addiction treatment.

TAX DOLLARS AT WORK!

According to press releases by both SAMHSA and ONDCP, http:www.samhsa.gov/ and http://www.whitehousedrugpolicy.gov/, respectively - , picked up by various papers on Nov. 6, the federal Government advocates disposing of "leftover drugs" in kitty litter to discourage "children, pets or drug abusers" who might be tempted to "stumble through the trash." The good news: Dr. H. Wesley Clark is quoted as acknowledging, "We don't want to assert that this is a panacea for the larger problem." Well, thank goodness our anti-drug leadership doesn't consider kitty litter disposal to be the panacea!

There is an associated warning that we NOT dispose of excess medication by flushing it down the toilet! Presumably "abusable" drugs can harm fish, though if they survive the other "stuff" that gets flushed down toilets, they have to have pretty tough constitutions.

Comments welcome.