7 May 2010

Pain and addiction conference New York City March 2010

Pain and addiction conference, Beth Israel Medical Center. Friday 19th and Sat 20th March 2010. Selected items summarized by Andrew Byrne.

“Emerging Practices in Pain and Chemical Dependency - 2010 Update on Opioid Therapy”

Times have changed since I attended a progenitor of this pain conference in New York in 1996. The present conference was held at the Times Square Marquis Marriott Hotel, starting promptly at 7.30am. The conference room was crowded with perhaps 300 attending. I sat in the front row, near convenor Dr Russell Portenoy, pain expert from Beth Israel Medical Center. Also present at the front were Ricardo Cruciani, expert on cardiac effects in methadone pain patients; Joyce Lowinson, editor of the big text on dependency; Herman Joseph; Mary Jeanne Kreek; Charles Inturrisi and Howard Heit. The latter is a close research colleague of Canadian pain and dependency expert Doug Gourlay. Other contributors over the two day conference were Lisa Marsch, Randy Seewald, Martin Cheatle and Edwin Salsitz.

Each speaker gave a list of potential conflicts of interest including sponsorship from drug companies. One quipped that in the past this declaration was considered a badge of honour. Nowadays however, we were told it was more a matter of shame! It is interesting to consider the different situations of speakers with one single declared conflict of interest over those with many. “Render unto Caesar …”.

Russell Portenoy gave an over-arching review of the state of play in the fields of pain management, dependency, practice guidelines and the political and research angles. He pointed out that unlike addiction treatment, pain management practice guidelines could not be based on evidence as the evidence in most areas was still rudimentary.

Howard Heit gave the second key-note dissertation entitled ‘Understanding risk in terms of chemical dependency: abuse, addiction and diversion during pain treatment’. In it he quoted his recent article with Dr Doug Gourlay (‘Universal Precautions Revisited’ 2009) with its ‘ten point rules’ for assessing risk of dependency. He called them his Ten Commandments. These carefully codify what should normally be done in good practice: history and physical; differential diagnosis; patient education and consent (oral/written); treatment trial; clinical review … and finally: careful documentation of each step. These are part of the clinical interaction which can help reveal features of substance use instability as well as the benefits or otherwise of current pain treatment.

Dr Heit also covered pseudo-addiction in the pain patient (usually diagnosed in retrospect). He reminded us that all medical interventions need an ‘exit strategy’, outlining a way of contracting with the patient what might occur if all else failed in the therapeutic relationship. He spoke about a “golden moment” in the patient’s ‘growth’ when they realised they are through playing games and are addicted. This acceptance of addiction and associated lack of control can be very moving. A Sydney colleague once described this, saying the patient always had a tear in the eye as it was related. We were reminded about the continuum between chronic pain and addiction and the need to treat according to individual need, utilising all the means at our disposal after non-opioid measures have failed … including dose supervision, urine testing, drug diary, counselling, adjuvant prescribing (eg. antidepressants, anxiolytics) etc.

Dr Ricardo Cruciani gave a talk about choice of opioid and matching patient to appropriate treatment. He placed opioid prescribing into its proper clinical context along with other physical, surgical, psychological, life-style and alternative pharmacological approaches. He advised that in the absence of clear evidence opioid treatment is still considered effective and ‘conventional’ in many clinical settings. We were reminded of the risks of all such prescribing: abuse, addiction, diversion and overdose. Dr Cruciani broached the rising incidence of deaths involving methadone which was explained by Herman Joseph in question time as being related to the recent expansion of its use in pain patients. The long half life of methadone has particular benefits in pain management but also requires that physicians be wary of dose escalations which can be toxic.

Dr Cruciani also gave one of the three morning break-out sessions entitled “Methadone Cardiac Toxicity”. I was disappointed that he used such a ‘loaded’ title when methadone has still not been scientifically proven to have any clinical cardiac toxicity and may indeed be cardio-protective. Methadone is associated with electrical changes to the QT interval which are nearly always asymptomatic. Dr Cruciani gave a roll-out of the literature with more about the ‘unknowns’ that the ‘knowns’. He argued that more research needed to be done, but did not seem to take into account the 2009 publication from Norway which has seriously questioned the worrying deductions of Chugh and Fanoe. Using indirect methods, these both concluded that torsade may be very common, yet Anchersen’s comprehensive national study did not find one single confirmed arrhythmia case out of 90 deceased methadone patients in a 7 year period in Norway (and only 4 unexplained deaths). Dr Cruciani correctly emphasised how little we know about torsade de pointes tachycardia and the (supposed) toxicity of methadone. This is probably due to the paucity of cases seen in regular dependency or pain practice. I continue to meet doctors who have worked full-time in this area for decades without seeing a single case of syncope due to torsade de pointes. Two experienced colleagues responded separately from Melbourne this month - one had just seen his first case, an older female alcoholic patient, the other had seen none in 20 years.

Rather than having cardiac toxicity, it is quite possible that methadone treatment (at least for addiction) promotes cardiac health as pointed out eloquently by Mori Krantz in his paper with Stewart Leavitt from 2001. These authors proposed a likely lower risk of endocarditis, dyslipidaemia interventions, blood pressure treatment and smoking cessation programs which are all likely to be more effective in those taking methadone than in those using street drugs. There is also some indication of lower rates of myocardial infarction in MMT subjects (Gross; Marmor). Dr Lisa Borg’s work has shown that higher doses of methadone can reduce cocaine use while the work of Forest Tennant has implied that in some cases, alcohol use may diminish in those prescribed methadone. Both of these could be expected to cause less cardiac irritability and lowered chance of torsade, quite contrary to the prevailing scare campaign.

It is to his credit that Dr Cruciani has consistently said that there is still no evidence to alter existing practice. However, he leaves the door open to further research which might do so … and that caution needs to be exercised regarding the risk of torsade tachycardia. It was just a shame that he did not separate the two clear clinical groups: the young, ‘uncomplicated’ opioid users or pain subjects who have virtually no risk of this complication … as contrasted with an older, more complex group in which torsade risk is a reality, albeit very low. Reddy’s study from Texas has shown prospectively that methadone is safe in cancer patients even though QT intervals are often raised even before patients were prescribed the methadone. All clinicians who prescribe methadone will have to learn to deal with this problem as our patients get older and other life-saving drugs are co-prescribed (most notably anti-virals and anti-fungals). However, at present few will encounter more than one or two in a clinical lifetime so collaboration is essential to elucidate the best ways to deal with torsade de pointes cases.

I asked Dr Cruciani a loaded question regarding the use of methadone in over a million patients under close supervision and whether the almost complete absence of confirmed torsade deaths and paucity of non-fatal torsade reports were not more reassuring than the prospective evidence he and his ‘expert panel’ were calling for. Dr Cruciani seemed annoyed at the question and alluded to my suggestion of ignoring the cardiac risk until it was proven. I had stated that doctors who were ignorant of the issue probably give their patients better quality treatment than those who worry over it, thereby restricting doses or using a less effective drug in cases where there is a choice.

Dr Cruciani said that he would not advise anyone to ignore this issue. The evidence is now overwhelming that the issue of possible cardiac toxicity of methadone has been fanned along by ignorance, a long-standing prejudice against methadone, and also by strong commercial considerations. The idea that “we” cannot afford to ignore possible cardiac toxicity of methadone ‘until it is proven’ says more about the litigious and commercial setting of medical treatment in the USA rather than about a sober balancing of clinical risk and benefit of this medication. My view is to treat all patients individually. The risk of torsade - and many other rare but serious events - can be stratified by using simple clinical details. Screening ECG was recommended by only one of thirteen citations given by Dr Cruciani (Krantz 2009 did; Krantz 2007 did not). A compulsory ECG in the present state of knowledge (or ignorance) is more likely to harm the patient than help them in my view. The largest literature review by Justo found that 85-100% of torsade cases had predisposing factors such as hypokalemia, structural heart disease, older age, QT prolonging drugs, drugs slowing methadone metabolism, female sex, older age, HIV status, alcohol use/withdrawal, stimulant use, inter alia.

The audience then heard two interesting talks on subjects a little more peripheral to doctors and patients in the fields of addiction and pain management. Firstly Mary Jeanne Kreek spoke about genetic aspects of addiction and the work her lab has been doing for over twenty years. While she gave an excellent summary of the natural history of addiction, I venture to say that, while fascinating academically and promising for the future, few if any of their recent scientific papers on the genetics question have been of direct benefit to patients or public health. Dr. Kreek also provided some interesting insights about the early days at Rockefeller University working with Drs Dole and Nyswander. Dr Kreek omitted to mention that it was in fact Dr Robert Halliday in Vancouver who first used methadone for opioid addiction between 1959 and 1964. There were, however, major conceptual differences (Newman, 2009).

Dr Charles Inturissi then spoke about ‘hyperalgesia’ in those taking opioids short and long term. Once again, apart from the obvious situations of withdrawal and break-through pain, the relevance of such albeit interesting findings of ‘priming’, conditioning and increased pain sensitivity in some at certain periods seemed some distance from the clinical setting. If patients are still in significant discomfort they deserve consideration of a higher dose of additional medication/modality for relief of those symptoms. Much of clinical medicine involves relatively simple ‘trial and error’ strategies while the complex diagnostics/therapeutics are more the exception than the rule in my experience.

A lunch time talk by FDA official Mark Caverly quipped about the space shuttle having a supply of opioids which had passed their expiry date and needed to be destroyed. This normally requires a visit from an FDA official but an exception was made and the expired drugs were put into a fatal orbit and was witnessed by Hubble telescope to burn up on re-entry to the atmosphere (laughter from lunchtime audience). It is a interesting that nobody even considered that perhaps American law would not extend to outer space! On a more serious note, we were told that the FDA did not visit doctor’s offices very often - and when they did they did so “to help”. There are American doctors in jail for what in many other countries would have been considered relatively minor infringements of technical regulations on prescribing. As Dr Caverly also pointed out (and as it is in Australia too), the standard of health care is regulated by the States and FDA and national legislation only has overarching responsibilities under the Controlled Substance Act of 1970 (‘TGA’ in Australia).

In the first session after lunch (of salad, poached chicken, followed by blanc-mange) Dr Steven Passik spoke about numerous new medications which are either in development or recently released which contain constituents which are aimed at less abuse. In each case he referred to certain benefits, most of which consisted of quite modest trends, that there were fewer subjects likely to misuse particular medications, the prototype being combination buprenorphine utilising naloxone (originally used and discredited and withdrawn in the early 1990s in New Zealand).

Dr Passik mentioned a combination of morphine with naltrexone (Embeda, approved by FDA in 2009). This hardly sounded possible until he revealed that the antagonist was contained in a vitreous bead in the center of the pill which would normally not be absorbed but would pass intact through the gut. The theory is that if drug mis-users crushed the pill indiscriminately they could get a rude shock if injecting anything containing naltrexone which is a long acting opioid antagonist. In certain circumstances it could also be quite dangerous, inducing persistent vomiting and dehydration (this was not discussed).

Another combination in the final stages of approval was hydromorphone in a viscous gel which it was believed would discourage injecting. Another method was to use the ‘push-pull’ osmotic controlled delivery system which also delayed absorption according to the membrane put around a tablet which may also have some short acting component for pain control. Oxycodone provided in waxy micro-particles is another as yet investigational product under trial at present (“Deter-Ex”). Yet another is the ‘Oros’ technology which has an internal membrane for slow delivery of drugs such as methylphenidate (already approved) and hydromorphone (under investigation).

Niacin (vitamin B3) can also be added to other drugs to induce an unpleasant flushing (‘niacin reaction’) if taken at certain high dose levels. This raises the issue that adding just about anything to an opioid will make is less attractive to drug users, just like adding anything to neat alcohol will do likewise for an undiscerning alcoholic.

Dr Passik was at pains to point out that for every combination and anti-abuse device developed, there were those intent on thwarting the attempts. He detailed various ways including differential dissolution in water or alcohol, chemically manipulating them or simply crushing tablets intended to be swallowed whole.

Dr Passik did not touch on the issue that these medications are invariably far more expensive than morphine, methadone, aspirin, acetaminophen or most of the NSAIDs (eg. ibuprofen). This is related to the new opportunities for drug companies to re-patent old drugs and secure higher prices for what are essentially cheap drugs with modest development costs compared to brand new drugs.

As with the possible abuse mentioned for these newer drug combinations, buprenorphine/naloxone is also abused, most commonly perhaps by existing buprenorphine patients who can inject the drug with impunity as happened in New Zealand in 1991 (see Robinson’s landmark paper in D&A Dependence - 1993 33;1:81-6). Due to its stronger affinity with the opioid receptor the naloxone apparently has little or no antagonist effect.

In question time Dr Passik was asked (by me) if there were any other areas of medicine in which a second drug of no immediate benefit to the patient was added to known effective medications in this way. He said that he was not, but that compulsory treatment for tuberculosis might have some parallels. He did not cite the old use of naloxone with methadone invented in the 1970s and reported at one of the very first methadone conferences. This was quickly dropped as a ‘useless precaution’ (see Barber of Seville, Rossini 1813).

Yet another of these ethicals was reportedly released for use in America in March 2010: a waxy new Oxycontin formulation.

In parallel to the research on diversion potential, there is not much carefully controlled comparative research to show equivalence of efficacy of these new formulations, nor was this required by the FDA in all cases, such as Suboxone. The only small pilot study (n=17) showed that changing to the mixed product required a 50% increase in dose for the average patient when compared to the pure product, Subutex. This has never been replicated in other studies to my knowledge. Dr Russell Portenoy had detailed to the audience the importance of differentiating the concepts of efficacy and effectiveness. “Efficacy” is the ability of the drug when administered to obtain the desired effects whereas “effectiveness” goes further and determines if the benefits outweigh the costs and side effects in the field.

Saturday’s opening plenary was by Dr Martin Cheatle from Philadelphia who spoke with clarity about the prevalence of chronic non-cancer pain and the consequences of inadequate treatment. These included delayed healing, depression, stress, suicide and addiction. Up to 50 million Americans may suffer from this at some time and as many as 40% reporting inadequate pain relief from treatment received. The conflicting pressures in primary care were broached, initially the essential nature of opioid prescription for serious pain, yet the reported increase in non-medical use of opioid drugs increasing four-fold from 1990 to 2002, up to 2.5 million citizens being involved.

The second day saw yet another talk about opioid regulations (State regulations by Dr Aaron Gibson of the Carbone Cancer Center in Madison, Wisconsin. He tried to reassure the audience that visits by regulators to doctor’s offices hardly ever happen and they are not in the business of putting doctors in jail. More than any other country, I understand that America convicts doctors for matters relating to psycho-active drug prescribing. Many of us have colleagues who have experienced it, and often in circumstances which, while always regrettable, are not always the ‘hanging’ offences they are made out to be by the authorities who seem to need to make an example of such souls.

At another session entitled “Office-Based Buprenorphine Therapy for Opioid Addiction: Lessons for Pain Management” Randy M. Seewald of BIMC gave an enlightened description of her lower Manhattan dependency practice. Having originally worked in the hospital and methadone clinic system, she found private office practice to be liberating as well as challenging. One main difference was that in her new ‘middle class’ subjects drug diversion was a minor concern rather than the constant bug-bear it can be in the clinic population. Although unable to prescribe methadone in parallel with buprenorphine, and despite having ties with the buprenorphine manufacturer, she was frank enough to say that if one could have only one drug, her choice would be for methadone.

Dr Seewald told us of the high retention rates in her practice … but this corresponded with low rates of successful withdrawal from buprenorphine – she only related one or two cases. In question time I raised the matter of smaller dose increments than 2mg in the virtually unbisectable Suboxone tablets. Dr Seewald had used the 2mg Subutex which can be broken in two but 0.4 or 0.2mg sublingual preparations are apparently not available in America (perhaps the company wants patients to remain on their drug for life!). There was a discussion about the legal but off-label prescribing of Suboxone for pain management which paradoxically in America requires no special licence as it does for addiction patients, even at the same dose levels.

There were other sessions on Veterans’ issues (crucial with the huge numbers now returning injured from the Middle East wars); CBT; Pain Guidelines; Nursing issues; Quality of life, amongst others. By this stage of proceedings, however, I found I was developing a type of medical Stendhal syndrome. This called for an authentic Italian meal and large glass of pinot grigio to restore my sanity - which was kindly provided at the invitation of my generous American hosts.

Comments by Andrew Byrne .. http://methadone-research.blogspot.com/


Krantz MJ. Clinical Concepts- Cardiovascular Health in MMT Patients. Addiction Treatment Forum 2001 No 4 http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388

Reddy S, Fisch M, Bruera E. Oral methadone for cancer pain: no indication of Q-T interval prolongation or torsades de pointes. Journal of Pain and Symptom Management 2004 28;4:301-303 http://www.redfernclinic.com/c/2009/11/methadone-safe-in-cancer-patients-with.php4

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338 http://www3.interscience.wiley.com/journal/118730811/abstract

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

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395 http://www.annals.org/cgi/content/full/0000605-200903170-00103v1

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

Gross ER, Hsu AK, Gross GJ. Acute Methadone Treatment Reduces Myocardial Infarct Size via the mu-Opioid Receptor in Rats During Reperfusion. Anesthesia and Analgesia 2009 109;5:1395-1402

Borg L, Broe DM, Ho A, Kreek MJ. Cocaine abuse sharply reduced in an effective methadone maintenance program. Journal of Addictive Diseases 1999 18:63-75 http://www.informaworld.com/smpp/content~db=all~content=a903861825~frm=abslink

Paulus I, Halliday R. Rehabilitation and the Narcotic Addict: Results of a Comparative Methadone Withdrawal Program. CMAJ 1967 96:655-659 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1936075/pdf/canmedaj01207-0020.pdf

Halliday R. Management of the Narcotic Addict. 1963 British Columbia Medical Journal 5(10):412-414 http://www.redfernclinic.com/c/2007/11/management-of-narcotic-addict-halliday_4512.php4

Newman RG. "Maintenance" treatment of addiction: To whose credit, and why it matters. International Journal of Drug Policy (2009) 20;1:1-3

Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965 193:646-50 http://jama.ama-assn.org/cgi/content/abstract/193/8/646

4 May 2010

Advice to stop methadone could be dangerous.

Methadone-associated Q-T interval prolongation and torsades de pointes. Stringer J, Welsh C, Tommasello A. American Jour Health System Pharmacy 2009 1;66(9):825-833 [*see new conflict statement]

Dear Readers,

This review examines the literature on cardiac events in methadone patients.  ‘Torsade de pointes’ arrhythmia and its accompanying prolonged, rate-corrected ’QTc’ interval are discussed in detail. The abstract states “A thorough patient history and ECG monitoring are essential for patients treated with [methadone], and alterations in treatment options may be necessary.”  Despite the extensive literature review, they give no specific justification for the controversial advice about ECG and ‘altered treatment options’.  Their own references would seem to indicate the futility of ‘screening’ ECG.

The authors quote 33 published torsade events in dependency subjects from 2002-2008.  My review of these indicates that 24 of the 33 give QTc interval information away from the torsade episode (and therefore away from the precipitating factor/factors which are usually involved).  Of the known 24 QTc intervals, 19 are ‘normal’ (460ms or less when enumerated) while only 3 are over 500ms, the interval where risk is thought to be significant. Hence, according to the case reports quoted by Stringer et al. screening ECG could not possibly detect or prevent cases of torsade de pointes in the great majority of such cases.  This is consistent with Justo’s literature review which also found precipitating events in 85-100% of published torsade cases he examined.  Krook questions the use of screening ECG as being the ‘wrong priority’. 

Stringer and colleagues also discuss in some detail two studies (Fanoe and Chugh), each of which concluded that large numbers of methadone patients may develop torsade.  Surprisingly, Fanoe also reported syncope, much of which he ascribed to torsade, in about 10% of his buprenorphine subjects. Both studies used indirect and ‘circumstantial’ methodologies to implicate methadone. Neither presented any actual cases of torsade de pointes. Nor did Wedam’s important RCT, another plank of this paper’s discussion, report any cases of torsade, despite high rates of QT prolongation (he is quoted here incorrectly as ‘Wedman’ on three occasions).

The conclusions of Chugh and Fanoe must now be in serious doubt after publication of Anckersen’s large national mortality series from Norway. This showed that despite prolonged QT intervals being common, their analysis of 90 deaths over seven years found that none was reportedly due to arrhythmia.  Unexplained deaths were rare with positive coronial findings available for all but four cases (in 2 of the 4 autopsy was not performed). Even if all four of these were due to torsade de pointes, an unlikely event, the incidence would still be extremely low.  Contrary to the claims of Krantz and colleagues (2009), the finding in Norway of so few unexplained deaths in methadone patients (<5%) is also consistent with other reports (Ballesteros 2003; Sorg 2002; Gagajewski 2003; Shah 2005).

From my reading on the subject over the years, I could find no confirmed deaths due to torsade de pointes in a patient being treated with methadone for addiction or pain. When this serious tachycardia does occur, it appears to be in older individuals with more than one risk factor, and, at least in methadone patients, appears to be non-fatal and treatable in most or all reported cases. 

Anckersen’s findings from Norway are also consistent with 40 years of research on methadone treatment showing that it reduces mortality substantially when used according to established guidelines (using adequate doses, supervision and psychosocial supports). 

Stringer, Welsh and Tommasello seem to ignore the potentially fatal consequences of their recommendations about “alterations in treatment options” based on ECG findings alone. Without any detailed explanation they blandly advise that buprenorphine ‘should be used’ in addiction subjects who develop prolonged QTc on methadone, despite the often impractical nature of such advice. Most such patients will be taking dose levels of methadone at which buprenorphine transfer is not recommended by the manufacturer. And this rather controversial advice is supported by just one single case report!

Good therapeutics dictates that successful treatment should only be change based on sound clinical evidence … and this is not produced in this paper. It is clear that for a substantial proportion of the opioid-using population there is simply no treatment that comes close to methadone maintenance regarding attracting, retaining and benefiting opioid dependent patients. And buprenorphine remains an excellent alternative for appropriate subjects.

*Please note also the up-dated conflict statement published in January 2010 edition: 

Am J Health Syst Pharm 2010 67:94
Methadone-associated Q-T interval prolongation and torsades de pointes (May 1, 2009, Clinical Consultation). On page 825, the author identification section should contain the following statement: Dr. Tommasello is Field Medical Advisor, Reckitt Benckiser Pharmaceutical Company, Parsippany, NJ, which manufactures buprenorphine–naloxone (Suboxone).

I hope this summary is of interest to readers.  [NOTE RESPONSE LETTER June 2010] http://byrnehallinanpubs.blogspot.com/2010/06/blog-post.html

Clinic web page: http://www.redfernclinic.com/c/
Concord Seminar blog: http://www.redfernclinic.com/concord/
Opera blog: http://www.redfernclinic.com/opera/critique/blog/


Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1

Justo D, Gal-Oz A, Paran Y, Goldin Y, Zeltser D. Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients. Addiction. 2006 101:1333-1338

Krantz MJ, Martin J, Stimmel B, Mehta D, Haigney MCP. QTc Interval Screening in Methadone Treatment. Ann Intern Med 2009 150;6:387-395

Krantz MJ, Garcia JA, Mehler PS. Effects of buprenorphine on cardiac repolarization in a patient with methadone-related torsade de pointes. Pharmacotherapy 2005 25:611-614

Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Addiction 2009 104;6:993-999

Fanoe S, Hvidt C, Ege P, Jensen GB. Syncope and QT prolongation among patients treated with methadone for heroin dependence in the city of Copenhagen. Heart 2007;93;1051-1055

Chugh SS, Socoteanu C, Reinier K, Waltz J, Jui J, Gunson K. A Community-Based Evaluation of Sudden Death Associated with Therapeutic Levels of Methadone. American Journal of Medicine 2008 121: 66-71