21 November 2008

Publications from Byrne Surgery in Redfern, New South Wales.

Byrne A, Hallinan R. HIV seroconversion. [letter] ANZ J Pub Health 2002 26;2:182

Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review 2002 21;4:405

Byrne A, Hallinan R. The introduction of buprenorphine into a medical practice treating addiction. Monograph Byrne Surgery March 03

Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus incidence among injecting drug users on opioid replacement therapy. ANZ Journal Public Health 2004 28;6:576-578

Byrne A, Hallinan R. Evaluation of accreditation of methadone clinics in NSW - Survey of clinics. Poster presentation 29;112 APSAD conference November 2004, Perth WA.

Hallinan R, Byrne A, Amin J, Dore GJ. Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. J Gastro Hepatology 2005 20;7:1082-1086

Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug Alc Dep 2006 81:129-136

Byrne A, Graham G, Hallinan R, Murnion B. Naltrexone implants as treatment for heroin dependence: Part I. Addiction Biology 2005 10:201

Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug and Alcohol Dependence 2006 81;2:129-136

Byrne A, Hallinan R. Methadone is still needed in addiction treatments. BMJ 2006;332:53

Hallinan R, Byrne A, Dore G. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated HCV-specific harm reduction. Drug Alc Rev 2007 26:437-443

Byrne A. Safe and effective opioid prescribing in addiction treatment. Monograph of article commissioned, accepted and rejected by Advances in Psychiatric Treatment journal 2008

Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency treatment setting, D&A Dependence 2007 88;1:49-53

12 November 2008

Methadone safe in young uncomplicated patients; check QT in older folk and those taking other drugs or alcohol, or with HIV.

Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Journal of Addictive Diseases 2008 27;3:31-35

Dear Colleagues,

These authors from Adelaide, South Australia report a relevant and reassuring ECG study from a 'normal' addiction clinic setting.

We are presented with a comparison of 35 methadone maintained patients, 19 on buprenorphine and 17 controls. Methadone doses varied from 15-145mg daily, being in the common range used clinically around the world. Most subjects were in their 30s and 28 of 71 subjects (39%) were female.

They report no significant difference between the mean corrected QT interval (QTc) of the three groups (407, 407 and 397 milliseconds). There was also no correlation found between methadone dose and QT interval. The QTc in those taking more than 60mg daily were slightly longer (405ms or 6.3%) than for those taking less than 60mg (381ms) (p=0.02). There were also some 'U' waves reported in the methadone patients. Two methadone patients and one control had prolonged QTc when defined as 430ms or longer for males (450 for females). No result was over 475ms. The threshold above which risk of torsade rises significantly is believed to be 500ms.

These findings are all consistent with the report of Lipsky et al. 35 years ago linking methadone prescription with QT prolongation and U waves. The clinical significance of these findings is still uncertain. These authors report no cases of torsade arrhythmia.

They conclude: 'Although an association is thought to exist between high methadone doses and elongated QTc, methadone and buprenorphine, at commonly used daily doses, remain safe agents for opioid substitution therapy.'

As a further exercise I contacted two prominent addiction experts in Adelaide (pop 1.2 million) on this subject. One had seen no cases and the other was aware of one possible case some years before. This is on a long background of good quality methadone treatment, both private and public, in that city.

It may be timely to examine the evidence for claims that methadone prescription in addiction treatment is accompanied by a significant risk from arrhythmias, including death. Despite there being no body of case reports in such guideline-treated subjects (or perhaps because of it) a number of authors have attempted to assess methadone's role in cardiotoxicity by using indirect and unconventional methods.

For example, Fanoe (ref below) prefers QT/torsade as an explanation for up to 30% of his subjects reporting syncope on MMT in Copenhagen. Since the incidence of torsade is certainly less than 1% annually, this explanation is not credible, especially coming from a country with extremely high alcohol statistics.

Chugh (ref below) used a methodology looking at post mortem structural heart disease in those dying suddenly with or without therapeutic levels of methadone in the blood. Their deduction for QT changes without a single case report seems hard to understand.

Wedam (ref below) wrote 'To compare the effects of [methadone] on the corrected QT (QTc), we conducted a randomized, controlled trial of opioid addicted subjects.' In fact they performed a retrospective re-analysis of old analogue ECG tracings from a 1990s RCT, finding more than 10% had QTc over 500ms. This is not consistent with other reports on the subject. No torsade cases were reported in the study groups.

A review of the world literature by Justo (ref below) found only 40 documented cases, 85% of whom had two or more risk factors. Few of these reported cases bear much similarity to those commencing 'normal' clinic or community addiction treatment. The QT/torsade cases tend to be significantly older, female sex, and to involve co-medications, very high methadone doses (up to 1200mg daily or ten-fold 'normal' doses) as well as certain metabolic (potassium or magnesium deficiencies) and genetic states (familial long QT syndrome).

I believe that it is now possible to restate unequivocally that 'normal', guideline-based methadone treatment is safe and effective. The cardiac arrhythmia issue appears to be based on a combination of factors rather than a consequence of standard methadone treatment. Knowing the other risk factors, most cases could probably be avoided using good clinical practice (see Sticherling). Routine pre-treatment cardiographs would have been unlikely to have detect any of these latter cases.

Even in the face of a dearth of relevant case reports, some have given advice to avoid methadone without due consideration of its benefits and the absence of a suitable alternative in a large proportion of cases, especially high-dose subjects (see Kakko). While methadone-induced torsade clearly can occur, the numbers appear to be exceedingly low and would probably be swamped statistically by reductions in endocarditis cases alone in those taking methadone (these and other benefits are eloquently reported by Krantz in 2001 - ref below).

In practical terms, this means that existing methadone patients needing other strong medications, methadone doses over 200mg or who develop HIV and/or have other risk factors should be recommended a cardiograph, just as they should have electrolytes, liver function tests, etc performed as a matter of clinical course.

We need to ensure that as clinicians we continue to ask the question: what is the evidence?

Comments by Andrew Byrne ..



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

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

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

Sticherling C, Schaer BA, Ammann P, Maeder M, Osswald S. Methadone-induced Torsade de Pointes tachycardias. Swiss Med Wkly 2005;135:282-285

Kakko J, Gronbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803

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

8 November 2008

Dr Mori Krantz on cardiac protections in methadone treatment. 2001.

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 (Archive accessed on 25/10/08 excerpt herewith)

A.T.F. Volume X #4 Fall 2001

Clinical Concepts- Cardiovascular Health in MMT Patients

By Mori J. Krantz, MD*

According to current estimates nearly 61 million Americans have one or more types of cardiovascular disease, including coronary artery disease (CAD), congestive heart failure, and hypertension.[1] Methadone maintenance treatment (MMT) patients are clearly part of this larger demographic, and there are unique clinical characteristics in this group warranting special attention.

High Risk, Less Access

Patients entering MMT are a very high-risk population from a general health maintenance standpoint. As a rule, patients who use illicit drugs expose themselves to a number of health risks, and are less likely to regularly interface with the healthcare system. An increased reliance on emergency services and a lack of integration into healthcare delivery systems create a backdrop for poor outcomes.

The literature confirms that barriers to high quality care for cardiovascular disease are greater in vulnerable patient populations, such as minorities and the poor. A great many MMT patients fall into both of those categories.

For example, African Americans and low-income patients are less likely to receive care by a cardiologist. In contrast, white race, higher income, and college education independently predict care by a cardiologist.[2]

Available data suggest that the gap in cardiovascular disease mortality between the poor and uneducated versus the wealthy and well educated has not lessened and may be widening. The National Conference on Cardiovascular Disease Prevention concluded that to attain the goals set forth by the U.S. Surgeon General�s Healthy People 2010 initiative, we should focus on reducing disparities in health status on the basis of race, ethnicity, and socioeconomic status.[3]

To make matters worse, mainstream physicians often stigmatize MMT patients. This further distances these patients from regular, preventive health care services.

Some Specific Cardiac Risks


Intravenous drug users (IVDUs) are at high risk for developing infections of their heart valves (infective endocarditis). These infections are a direct result of bacteria entering the bloodstream at the skin site of injection.

Acute infection accounts for the majority of hospital admissions among IVDUs and endocarditis is found in 10% of these episodes.[4] Most of these patients have no pre-existing cardiovascular disease.

The symptoms of this disorder may include persistent fever, chills, sweats, muscle and joint aches, malaise, and back pain.[5] These symptoms are invariably preceded by an episode of intravenous drug use.

Endocarditis has very high morbidity and mortality. It can necessitate extended intravenous antibiotic therapy and in many patients will require complex heart valve surgery or even valve replacement. Other consequences of endocarditis include brain abscess, kidney failure, and death.

MMT offers substantial protection from this deadly disease by eliminating or dramatically reducing the amount of illicit drug use. In our local hospital experience during 2000-2001, practically none of the heroin-abusing patients admitted with endocarditis were in methadone treatment programs.

Furthermore, in my oversight of hundreds of MMT patients during nearly a decade, I have encountered only 3 cases of endocarditis in that population. This evidence is anecdotal and retrospective, but supports the common sense notion that methadone treatment dramatically reduces the risk of endocarditis in IVDUs.

Coronary Artery Disease (CAD)

CAD is the number one cause of death in the Western world [1] and MMT patients are no exception. These patients may be at particularly high risk given that as many as 90% of them smoke tobacco, which is a known risk factor for CAD.[6]

Additionally, cocaine abuse is seen with some frequency in this population. Cocaine use has been linked to the development of arrhythmias, CAD, heart attack, and death.[7]

Despite the uses of tobacco and cocaine in MMT patients there have been no published reports documenting a higher overall incidence of cardiovascular disease in these patients. In my MMT practice, there are very few patients with established CAD. This is remarkable, given the fact that a significant proportion are beyond 50 years of age and many continue to smoke cigarettes.

Is there a possible explanation for this relatively low incidence of CAD in MMT patients?

The evidence is not clear. However, there is some pharmacologic data suggesting that methadone may exert a calcium channel blocking effect.[8] Calcium channel-blocking medications lead to slower heart rates and reduced cardiac work, and these agents are effectively used to treat CAD patients who develop symptoms of angina (chest pain).[9]

Also, opiates, including methadone, are known to reduce blood pressure and slow the heart rate. Morphine, for instance, is a commonly used medication to treat hospitalized patients who experience a heart attack.

Thus, due to these properties, methadone is theoretically protective in preventing or reducing cardiac ischemia (lack of blood supply to the heart).

Cardiac Arrhythmias

There is no compelling evidence in the literature to suggest that methadone treatment is a direct cause of sudden cardiac death or fatal heart rhythm disturbances.

In clinical practice, the risk of cardiac arrhythmias attributable to these treatments currently appears to be quite small. Future research and accurate incidence data will help clarify any contribution of opioid-agonist therapies to arrhythmia risk.

MMT Minimizes Cardiac Risks

Ongoing participation in MMT affords patients many heart health benefits. For one thing, these patients have significantly greater access to preventive cardiac-health services than opioid-dependent persons not in treatment.MMT patients are provided periodic monitoring of their blood pressure and pulse. Vital signs are obtained upon admission, during yearly physical exams, and during dose changes.

In my experience, this has offered a tremendous opportunity to screen patients for hypertension and then provide adequate treatment. Hypertension afflicts 50 million Americans; it is a leading contributor to CAD and the number one cause of stroke.

In my practice, a full lipid panel is obtained annually in all patients to check cholesterol levels. Those with elevated levels can be offered effective treatment with cholesterol-lowering medications, which have clearly been shown to reduce the risk of heart attack and death in patients who are at high risk.[10-12]

Finally, patients in MMT have access to frequent professional counseling, which presents ideal opportunities for discussing the importance of smoking cessation for long term cardiac health. The most common cause of death in smokers is coronary artery disease (CAD).

Stopping smoking dramatically reduces the risk of future heart attack or death. We regularly counsel patients on tobacco risks and many are able to quit or significantly reduce tobacco consumption as part of comprehensive treatment plans.

In conclusion, from a cardiovascular perspective, methadone is a safe medication and MMT program staff can perform vital roles in providing effective cardiac risk-reduction services.


1. American Heart Association. Heart and Stroke Statistical Update; 1999.

2. Auerbach AD, Hamel MB, Califf RM, et al. Patient characteristics associated with care by a cardiologist among adults hospitalized with congestive heart failure. J Am Coll Cardiol. 2000;36:2119-2125.

3. Cooper R, Cutler J, Desvigne-Nickens P, et al. Trends and disparities in coronary heart disease, stroke and other cardiovascular diseases in the United States. Findings of the National Conference on Cardiovascular Disease Prevention. Circulation. 2000;102:3137-3147.

4. Murphy JG. Mayo Clinic Cardiology Review. 2nd ed. Philadelphia: Lippincott Williams & Wilkins; 2000:412.

5. Mandell GL. Principles and Practice of Infectious Diseases. 4th ed. Churchill Livingstone; 1995:748.

6. Practitioner panel: methadone and heart health. Addiction Treatment Forum. 2001;10(3):5.

7. Lange RA, Hillis LD. Cardiovascular complications of cocaine use. N Engl J Med. 2001;345:351-358.

8. Lee CH, Berkowitz BA. Calcium antagonist activity of methadone, l-acetylmethadol and l-pentazocine in the rat aortic strip. J Pharmacol Exper Ther. 1980;215(1):259-265.

9. ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina. J Am Col Cardiol. 1999;33:2092-2190

10. Long term treatment with pravastatin in ischaemic disease (LIPID) study group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349-1357.

11. Scandinavian Simvastatin Survival Study Group. Randomized trial of cholesterol lowering in 4444 patients with coronary heart disease: The 4S trial. Lancet. 1994;344:1383-1389.

12. Sacks FM, Pfeffer MA, Moye LA, et al. Cholesterol and Recurrent Events Trial Investigators. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med. 1996;335:1001-1009.

*Mori Krantz, MD is Director of the Cardiovascular Risk Reduction Program, Denver Health Medical Center, and Assistant Professor of Medicine and Cardiology, University of Colorado.