METHADONE MISUSE/ABUSE - A NEW PATTERN IN USA?

From the Upper Peninsula, Michigan, comes a report of an increase in heroin dependence. Police officials there are quoted as saying the dependence in many instances is initiated by misuse - including by injection - of methadone prescribed for pain: "... doctors are prescribing methadone ... and the people who are becoming addicted to it are basically becoming heroin addicts." This may be - but for decades there was no evidence in America that methadone misuse by injection was a problem of any significance, or that it was the initial opiate used by those seeking treatment for addiction. Click for the full news article from Michigan:

POSSIBLE IMPACT OF METHADONE ON QT-WAVE PROLONGATION:

From our colleague, Andrew Byrne, MD in Australia, the following observations regarding QT-wave prolongation:

QTC Interval Prolongation and Opioid Addiction Therapy. Baker WA, Krantz MJ. Archives Internal Medicine (letter) 2008 168;14:1502

Dear Colleagues,

In this letter Baker and Krantz applaud Wedam et al’s ‘commendable’ “addition to the medical literature” which found QT prolongation in 23% of methadone subjects. In fact these researchers found much the same as Janet Lipski’s report from 1973 (34%). Thus it is clear that a substantial minority of methadone patients have modest prolongation of QT intervals of uncertain significance.

Baker and Krantz then express the unsurprising deduction that if a lower cut-off for QT prolongation were used, a correspondingly higher proportion of prolongation subjects will result (up to 50%). The clinical significance of these observations, if any, is not detailed. Indeed, not a single subject in the entire study had a QT interval (corrected) of 500ms or more which is considered by some authorities to be the clinically significant cut-off for risk of tachycardia. And none developed tachycardia.

Krantz has wrongly cited Lipski’s study as being (at least in part) to investigate sudden deaths in methadone patients. In fact, Lipski and colleagues were concerned about heroin deaths and the QT findings in methadone patients were incidental. When this mistake was pointed out in Lancet, Krantz in reply ignored the matter and turned to increasing deaths of non-addiction treatment (pain) cases in America more recently (Mehler 2007).

Specifically, Krantz writes that Lipski’s study was aimed at investigating “a perceived increase in the risk of sudden death in heroin addicts, even in those successfully treated with methadone” in 1973 in New York (Krantz MJ 2006). From the title and opening lines it is clear that Lipski and colleagues were actually concerned over deaths in heroin users where sometimes blood levels were not particularly high, an issue raised by long time city coroner Dr Milton Helpern (see ref). They performed cardiographs in new methadone applicants who had used street heroin in the previous hours or day(s) to see if there were any electrical disturbances which might explain the sudden deaths in heroin users.

Unlike in his first paper on this subject, Krantz now treats QT prolongation in isolation as if it were a complication in itself, avoiding discussion of torsades or other cardiac events. And like most of the other studies, Wedam and colleagues report no symptomatic heart disease whatever and, most importantly, no sudden deaths. Over a period of 30 years of intensive, supervised prescription of methadone only one single case of arrhythmia was reported to the FDA (Pearson). So while torsades or ventricular fibrillation occur in methadone patients, the prevalence must be very low and possibly near to the rate in the general population (estimated to be 1 in 2000 - see Smith W).

This laudatory letter is just another ‘weak link’ in the case put by Krantz that due to potential cardiac complications, methadone treatment needs to be reviewed, especially when used in high doses. He recently noted ‘with consternation’ (hardly a scientific term) that higher doses were being used in addiction clinics in his own state, something most public health specialists would have applauded (D’Aunno). Many rigorous studies indicate that higher doses protect dependency patients from significant and measurable events (overdose, viral disease, criminal behaviour, depression, etc). Dole’s seminal study of methadone treatment reported up to 180mg daily with excellent results and no serious side effects.

To my knowledge there have still been no reported series of confirmed case reports of cardiac complications (eg. torsades-de-pointes) in patients receiving methadone treatment for addiction under existing guidelines. Krantz emphasises the proven benefits of MMT yet at the same time questions this established, evidence-based practice, emphasising a difficult therapeutic “trade-off”. Yet this is before there is documented evidence of a problem existing and despite 30 years of careful research showing safety and effectiveness. Further, there has been no analysis of the costs and benefits of any suggested alternative strategies such as low dose methadone or transfer to buprenorphine. Krantz has also apparently had minimal input from dependency specialists. Few non-cardiologists would be so bold regarding advice on heart treatments.

Dr Krantz's widely publicized views have had the consequence of denigrating methadone as a treatment for both addiction and chronic pain. I can find no evidence suggesting that any cases of cardiac complications resulting from methadone treatment have been avoided as a result. The literature reveals only flimsy and conflicting evidence - most of it retrospective - of an association of methadone and cardiac events. Some have reported a lower cardiac risk (Marmor 2004).

Krantz's articles, letters and personal communications show a clear 'disconnect' between his earlier findings and the sentiments he has expressed more recently. While his earlier findings relate mostly to pain patients, he has strongly targeted an addiction treatment audience for his communications and further research (eg. Krantz 2007). His advice, which has changed over the years, has involved (1) the need (or otherwise) for a cardiograph before starting treatment, (2) the avoidance of methadone where possible and (3) the avoidance of high doses where methadone is used. His other recommendations are purely generic in recommending careful history and physical on each patient and acting on any evidence of cardiac risk. While this is important, it is probably no more important than acting on evidence of infectious disease, overdose risk, liver disease, allergies, mental illness, etc, etc.

The potential risk of cardiac side effects must be balanced against the unequivocal benefits of methadone maintenance to those who need and want it for their condition. There need be no ‘competition’ with buprenorphine which is an excellent alternative with certain benefit and certain disadvantages in the opiate treatment population.

References:
Wedam EF, Bigelow GE, Johnson RE, Nuzzo PA, Haigney MCP. QT-Interval Effects of Methadone, Levomethadyl, and Buprenorphine in a Randomized Trial. Arch Intern Med 2007 167;22:2469-2473

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

Mehler PS, Krantz MJ. Authors’ reply. Methadone and QTc prolongation. Lancet 2007 369:366-7

Smith WM. Cardiac repolarisation: the long and short of it. MJA 2008 188;12:688-689

Lipski J, Stimmel B, Donoso E. The effect of heroin and multiple drug abuse on the electrocardiogram. American Heart J 1973 86:663-8

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

D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50 '193(8) 80-84'

Helpern M. Fatalities from narcotic addiction in New York City : incidence, circumstances and pathologic findings. Human Pathology 1972 2:13-21

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

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

Leavitt S. Methadone: facts and fiction http://www.atforum.com

METHADONE IS A MEDICATION, SO 'USER' IS THE WRONG WORD:

Below is a LTE that was published in the Vancouver Sun, I wanted to share:

Re: Methadone users 'get pharmacy kickbacks,' Sept. 9

No one could fail to condemn people who are alleged to accept bribes such as this -- or, especially, those who offer them.

But The Sun's reporters and editors should reflect on the use of the term "methadone users." Whatever the intent, the clear message is one of disdain. These individuals receive a medication from specially licensed physicians as part of a treatment regimen known for 40 years to be highly effective.

Can you imagine describing diabetics, even those who are woefully non-compliant with medical advice, as "insulin users"?

PLACEBOS ONLY JUSTIFIED IN STUDIES WHEN NO EFFECTIVE TREATMENT IS AVAILABLE:

A brilliant article just appeared in the British Medical Journal documenting the total absence of "placebo-controlled random assignment clinical trials" that "prove" that it really is the parachute that protects against injury and death when people jump out of airplanes. Those experts and politicians who demand ever more and more clinical trials to prove what is already known, or what is intuitively clear strictly on a common sense basis, should take heed.

Sure there are a great many clinical interventions where placebo is indicated. But the Helsinki Convention clearly states that placebos are only justified when no treatment is available that is known to have a modicum of efficacy. Meanwhile, more and more studies on detoxing opioid-dependent people, maintain patients with opioid agonosts, track long-term recidivism rates, etc, etc, etc, utilize hapless "control" groups that receive placebo, and whose death rate in the studies are not infrequently the basis for concluding that placebo aren't so great in absolute or relative terms.

For article:

ADDITIONAL POST SEPT 25, 2008

SUBCUTANEOUS BUPRENORPHINE YIELDS "STATISTICALLY SIGNIFICANT RESULTS COMPARED TO PLACEBO FOR OPIOID ADDICTION:
urine test results are not cited, but are said to have been better for buprenorphine subjects; one-third of buprenorphine subjects and 69% of placebo recipients dropped out within 6 months. Ethical issues are not mentioned in the report by Titan Pharmaceuticals. Full report (July 29, 2008)

HOW MANY MORE ADDICTS TO BE SUBJECTED TO PLACEBO?

It is difficult to comprehend how any trial of a new medication or route of administration can be tested against placebo in the treatment of addiction (see news item this site, 18 Sept 08). A million people worldwide receive "substitution" treatment with oral opioid agonists; this treatment has (for over a quarter century!) been declared effective by the US government, and has also been endorsed by the Institute of Medicine, by WHO/UNODC/UNAIDS, and by the authorities of many dozens of countries that have approved its use. How can researchers and their academic institutions and "review boards" continue to condone placebo trials? And why would FDA apparently demand that hapless addicts seeking care be recruited into placebo-control trials when approval of a new treatment is being sought?

As for the results touted by the company: so subcutaneous buprenorphine was "statistically" better than placebo in terms of urine tests and retention - so what? Is someone counting the number of instances of HIV transmission, arrest and incarceration, destroyed families, and deaths among the placebo subjects? No ethical provider would ever consider putting an opioid dependent person on placebo, so its lack of efficacy compared to some new drug or means of administration is a total irrelevancy! And yet the results of this "study" have been heralded by one of the principal investigators as being "very promising," asserting the "success of [the medication] should have a very significant impact on our ability to effectively treat opioid addiction."