19 July 2013

Adverse Event reports should inform clinical medicine but this is cardiac alarmism at its worst.

QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Pani PP et al. Cochrane Database CD008939
 
Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Kao D et al. Ann Intern Med 2013
 
Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Wedam EF, Haigney MC. Addiction 2013
 
False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H et al. J Pain Res 2013 [full citations below]
 
 
 
Dear Reader,
 
Before commenting on these four recent items, here is my summary of the state of play: While distressing and serious, torsade de pointes tachycardia is a very rare event in methadone patients.  This arrhythmia is highly treatable with a low or zero mortality rate judging from the cases reported in the literature since 2002 (n~100).  Torsade de pointes appears to affect the older patient population (>40 years), is more common in women and generally when higher doses of methadone (>120mg daily) are combined with other drugs such as certain antibiotics and anti-virals. 
 
These four recent items related to cardiac complications in patients prescribed methadone.  While the Cochrane review finds insufficient evidence to advise any interventions on this subject, the other three papers are disappointingly thin on facts and high on the fog factor despite the clarity now appearing after a decade of clinical experience since Krantzs seminal report of 17 cases in 2002.  [Cochrane abstract: http://www.ncbi.nlm.nih.gov/pubmed/23787716?dopt=Abstract ]
 
Kao, Krantz (senior and corresponding author) and colleagues purport to present an analysis of FDA adverse event reports.  Their torsade figures include reports which were not primarily due to methadone (43% not primary suspect) and further, it also comprises reports of QT prolongation without a break-down of these two very different syndromes.  Hence to arrive at the actual number of torsade reports where methadone was the primary suspect one needs to discount 361 by 43% and then take account of the proportion of torsade cases (figure not given here but was about 70% in Pearsons paper).  This makes about 2 reports of torsade tachycardia per month in America.  About half would have been dependency cases (FDA information).  See my own more detailed description and conclusions [ http://methadone-research.blogspot.com.au/2013/07/can-adverse-event-reports-inform.html ].  [Abstract can be accessed here: http://www.ncbi.nlm.nih.gov/pubmed/23689766?dopt=Abstract ]
 
 
In an Addiction editorial Wedam and Haigney write discomforting and confusing words about the so-called QT prolongation phenomenon.  Why call it a phenomenon any more than a fever in an infant with an infection?  But it serves to spice up the mystery which scientific discourse is meant to dispel.  Many commentators and public health authorities have called for more substantial research on this subject, preferably national surveys.  Yet now that such research it to hand from Norway and France (sudden deaths in Norway and torsade reports in France, all very reassuring and consistent) many writers seem to ignore its outcomes.  Wedam and Haigney cite the Norway article by Anchersen but then states that Americans must be different to Europeans!!  Their citations do not (and cannot) justify such a position, making the contention no more than a ruse to confuse. 
 
This Addiction editorial continues a long history of apparent antagonism to methadone treatment.  Their titles would seem to support this while few of the items would appear to be productive issues aimed at improving patient care or public health goals.  Topics included cravings from additional methadone, memory problems, injecting of methadone, benzodiazepine abuse, deaths, and more. [full Addiction article available on line: http://onlinelibrary.wiley.com/doi/10.1111/add.12123/full ]
 
 
The third item is a chronic pain case report of such an extraordinary nature that it can have little or no relevance to regular clinical practice.  Veteran author Dr Cruciani (senior and corresponding author) and colleagues surprisingly publish a detailed day-to-day report of a complex pain patient who was clinically overdosed with methadone given parenterally along with pethidine and other opioids.  The most telling features relative to cardiac safety would include: the lowest QTc values (317, 416ms) were found on the days after the highest methadone doses (334, 363mg).  One slightly prolonged reading (451ms) occurred two days after methadone was ceased altogether.  These findings are consistent with the literature in which normal QTc levels were commonly found in patients who had torsade de pointes away from the tachycardia episode (and also large diurnal variations in QTc values).  A single ECG tracing is almost certainly a waste of time for routine purposes in low or perhaps even high-risk patients.  And despite all the prolonged QT levels this patient still did NOT develop any arrhythmia. 
 
 
While torsade de pointes is extremely uncommon, it will still be seen occasionally in dependency and pain practice.  The arrhythmia needs to be considered in someone with fainting, fitting, palpitations, shortness of breath or occasionally, chest pain.  Treatment involves the use of urgent paramedic treatment and transfer to cardiac intensive care for monitoring.  Some patients will need intravenous magnesium, temporary pacemaker and/or cardioversion.  Withdrawal or replacement of the suspected drugs and/or reduction in doses may be useful.  There is no single agreed protocol for this condition but its treatment should be directed by cardiac experts, just as dependency should be directed by dependency experts and pain by pain management experts. It is crucial not to avoid appropriate doses of methadone as the risk of inadequate doses is very substantial, including death, whereas there he never been a reported confirmed death due to torsade de pointes.
 
As Pani et al. point out there is no proven preventive strategy but it would seem prudent to order a cardiograph on patients who are prescribed high dose methadone (>150mg), especially if there are any other risk factors.   
 
Comments by Andrew Byrne ..
 
Full citations for these articles:
 
Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database Syst Rev. 2013 Jun 20;6:CD008939
 
Kao D, Bucher Bartelson B, Khatri V, Dart R, Mehler PS, Katz D, Krantz MJ. Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Ann Intern Med. 2013 21;158(10):735-40
 
Wedam EF, Haigney MC. Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Addiction 2013 108;6:1015-1017
 
False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H, Hao J, Cruciani RA. J Pain Res 2013 6:375-8