Agonist substitution - a treatment alternative for high-dose benzodiazepine-dependent patients? Liebrenz M, Boesch L, Stohler R, Caflisch C. Addiction. 2010 Apr 27 Early View
Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. D&A Review 2010 29:3:250-255
Dear Colleagues,
Two prominent recent articles have highlighted an often neglected problem area for drug users in treatment. Benzodiazepine use/abuse has long been the ‘elephant in the room’ in addiction treatment. It is surprising to me that a ‘Just-say-no’ approach is often espoused for this particular problem where ‘harm reduction’ is the principle underlying public health and medical treatment in recent years. Yet we know that benzos, along with alcohol, constitute a major source of harm in the drug using population.
Darke and colleagues report that tranquillizer use parallels both physical and mental deterioration. This 3 year, prospective longitudinal study finds that initial use of benzodiazepines did not, however, predict poor progress in the medium to long term. Their study group included patients entering pharmacotherapy, detoxification and rehabilitation services as well as a non-treatment group recruited from community harm reduction services (needle services).
It is possible that much of this harm may be preventable given an appropriate approach. Benzodiazepines also feature prominently as an association in mortality reports by Darke and others.
In an editorial in Addiction, some Swiss workers propose ‘agonist substitution’ as a hypothesis which needs formal testing. They point out the differences with methadone maintenance as well as some similarities. They further detail possible problems, especially with shorter acting or injectable preparations. However, they also emphasise the known dangers of ignoring this issue when, despite current interventions, a high proportion of users remain unable or unwilling to withdraw from these drugs. From reports over many years we know that there is a wide regional variation in use with relatively low levels in some American cities (<10% dependent) up to very high levels reported in Israel (>50% in some clinic populations).
Over the years I have interviewed many clinicians about the question of prescribing benzodiazepines to dependent patients. My findings have been that the great majority of experienced clinic doctors have authorised supervised dispensing of long acting benzodiazepines, usually diazepam, in short or medium term use for at least some patients. Most, however, have been reluctant to do so long-term or for large numbers of patients in the absence of clear guidelines on the subject.
This lack of an accepted protocol is partly due to a lack of research evidence. Yet benzodiazepines, like opiates, are still prescribed widely in the general population for insomnia, anxiety and panic disorders, even if their use is not first line. Hence we should ensure that we strike the right balance between discouraging their use and making them available in a manner which is safe. Only a very small proportion of those who are prescribed benzodiazepines develop dependency problems, precisely as also occurs with opioids for pain. Overall sedative prescribing has dropped significantly over the years but some preparations have seen surges in recent years such as alprazolam. Flunitrazepam has been subject to certain restrictions in Australia and was never been approved/marketed in the United States.
There is no dispute about the use of diazepam in alcohol withdrawal, status epilepticus and panic disorders (see various expert guidelines). While its effectiveness for insomnia and anxiety is limited by tolerance, most GPs still use benzodiazepine prescription in some cases. Hence there is a case for benzodiazepine availability in dependency clinics, even if just to avoid prescription of large quantities unsupervised from other doctors. Whether this should be available low-term or high-dose is still controversial. Yet such a practice could be seen potentially as a “harm minimization”, knowing that quite the opposite can easily occur with community prescribing of unsupervised or “on demand” prescriptions.
Thus smaller quantities and increased supervision may be consistent with improvements to measurable indices of stability in dual addicted patients. The safest would be one tablet per day with all tablets being supervised … yet this may not be acceptable to some patients and may not be practicable in the clinic/pharmacy setting. It is certainly a time consuming enterprise and could not possibly be offered to large numbers of patients without specific funding. And such funding is unlikely to be provided without more formal research to demonstrate safety and effectiveness of such an approach.
Comments by Andrew Byrne ..
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/
References:
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
http://www.ijdp.org/article/S0955-3959(08)00165-5/fulltext
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
“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/
References:
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
http://www.ijdp.org/article/S0955-3959(08)00165-5/fulltext
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:
Correction
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/
References:
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
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:
Correction
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/
References:
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
9 April 2010
New York City public lecture on HIV medicine and public health.
Public Lecture at NYC Health Department under auspices of Mayor Bloomberg. 2pm Thursday 18th March 2010
This City Department of Health public lecture started with some rather complex statistical formulae of how to deal with missing data in studies of the natural history of HIV seroconversions. Michelle Shardell PhD had ‘inherited’ a job on a long term project (ALIVE or AIDS Linked to the Intra-Venous Experience) which started, she said, while she was still in school (1988). It enrolled 3000 HIV negative injectors and ordered twice yearly blood testing to determine ‘natural’ rates of seroconversion.
Professor Shardell described the problems of having reams of data but where much was incomplete and how best to draw the correct conclusions by approximating missing data. She discussed the conflicting possible biases of those who miss blood test appointments, some because they may have been well and busy with life … while others may have been unstable and unhappy, using drugs and alcohol, being unemployed and/or engaging in high-risk behaviours and thus missed their blood test.
We were introduced to a complex set of sigma formulae which were supposed to account for missing periods in otherwise long-term data. It was a little disappointing that we were given virtually no outcome data of the study, some details of which I looked up later on an internet search.
On the other hand, Dr Don Des Jarlais quoted HIV prevalence figures for several American cities, Miami, New Orleans and Washington DC were amongst the worst with near 30% of injectors estimated to be HIV positive. In other cities, I understand, including Tucson, Seattle and St Louis, the figure was much lower, some even as low as 1% amongst injectors. In several major centres, the figure was not available.
The message was emphasised that good research from New York had shown that for injectors who began injecting before 1995 the rates of HIV was substantially higher than for those who started afterwards, in just about every category of risk. New York, unlike the rest of the country, had reasonably good access to opioid maintenance treatments as well other harm reduction services such as needle “exchange”, as it is still quaintly termed here. And it largely functions in the US as just that – ‘exchange’ new for old (imagine if we did that for condoms!). We were reminded that the proportion of dependent individuals currently on opioid maintenance treatment (OMT) was calculated to have risen from 6 to 8 percent in America, showing only a modest improvement over ten years. We were reminded also that “secondary needle exchange” (pass-it-on) was vital to the success of the intervention wherein non-addicts (sometimes called ‘alcoholics’) would make small profits by returning used needles and obtaining clean supplies to be sold/distributed at a later time for money.
Dr Des Jarlais is far too experienced to lecture Americans about foreign findings yet he subtly dropped two pearls into the mix towards the end of his presentation in lower Manhattan. He had discussed and described some of the needle services here in American cities and then told the audience that (‘tiny’) New Zealand had over 600 needle exchanges while there were only about 300 in the whole of America. He alluded to the changes in federal funding for such preventive interventions but pointed out that it will take some years for such policy change to filter down to ‘street level’. In a reference to Australia our speaker also pointed out that most of the few drug injectors who contract HIV do so from sexual exposure rather than from needles (while up to 7000 Americans do so annually from contaminated needles if we are to believe the figures).
The correlation between past genital herpes simplex infection and HIV was reiterated, pointing out the behavioural and physical reasons involved. This was clarified further during question time.
While Don Des Jarlais did not quote the HIV rates in New Zealand I had done so privately with the City Health Department official Lucia Torian before she opened the session - which was delayed slightly due to new and inordinate security introduced (all visitors were photographed and ‘branded’!). She had responded to my comment that a number of countries had avoided the HIV plague, saying that I must be referring to Russia, Ukraine and North Korea where there is still denial of the existence of the epidemic in some circles. I said that in fact I was referring to Hong Kong, Australia and New Zealand. Following another off-hand remark she made, I told her that each time I mentioned this to Americans I was either disbelieved or derided, just as she was doing.
Dr Samuel Friedman acted as discussant and in half an hour elaborated some details of the presentations. He commended Dr Shardell on her study but commented that rather than only seeking views of academic experts the team might do better to include the views of knowledgeable drug users. Such folk are readily available and many have a lot to contribute. On that subject, I once asked Professor Vincent P. Dole his opinion about a new secure medicine container. He said that before giving his views he would rather hear the views of a few drug use patients.
Dr Friedman pointed out the large number of major US states and cities which no longer publish official figures on HIV cases. His personal greatest worry in epidemiology was when data was not being collected so that knowledge of the public health issues could be swept under the carpet.
Further, we were told of a study done by Dr Friedman, Des Jarlais and colleagues which showed that the different modes of transmission depending upon the infected pool involved in a given population. Where the prevalence in injectors was >20% already, some behaviours (eg. needle sharing) were directly correlated with seroconversion. Where rates of HIV were <9% risk behaviours were not statistically associated with seroconversion but rather the predictors reflected whom they injected among. We learned that the New York rate was between 9 and 20%. There was also some discussion of arrest rates, socio-economic areas and seroconversions and some research linking them.
I mentioned to Dr Des Jarlais that Hawai’i appears to have the best organised and most widespread needle availability in the US, some of which I saw on a recent visit. Dr Des Jarlais told me he was aware of that since in fact he was the official evaluator for the State’s harm reduction project! That man is everywhere! I recall that he spoke at one of the first Methadone Conferences in Sydney almost 20 years ago, warning us about the threat of HIV and the means to prevent a second wave in drug users. His advice was timely and his campaign to implement better public health strategies continues unabated. More strength to him - and his colleagues! And thanks to the New York City Health Department for sponsoring these public lectures, and allowing strays like me in.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
Opera blog: http://www.redfernclinic.com/opera/critique/blog/
New York in spring: http://ajbtravels.blogspot.com/
This City Department of Health public lecture started with some rather complex statistical formulae of how to deal with missing data in studies of the natural history of HIV seroconversions. Michelle Shardell PhD had ‘inherited’ a job on a long term project (ALIVE or AIDS Linked to the Intra-Venous Experience) which started, she said, while she was still in school (1988). It enrolled 3000 HIV negative injectors and ordered twice yearly blood testing to determine ‘natural’ rates of seroconversion.
Professor Shardell described the problems of having reams of data but where much was incomplete and how best to draw the correct conclusions by approximating missing data. She discussed the conflicting possible biases of those who miss blood test appointments, some because they may have been well and busy with life … while others may have been unstable and unhappy, using drugs and alcohol, being unemployed and/or engaging in high-risk behaviours and thus missed their blood test.
We were introduced to a complex set of sigma formulae which were supposed to account for missing periods in otherwise long-term data. It was a little disappointing that we were given virtually no outcome data of the study, some details of which I looked up later on an internet search.
On the other hand, Dr Don Des Jarlais quoted HIV prevalence figures for several American cities, Miami, New Orleans and Washington DC were amongst the worst with near 30% of injectors estimated to be HIV positive. In other cities, I understand, including Tucson, Seattle and St Louis, the figure was much lower, some even as low as 1% amongst injectors. In several major centres, the figure was not available.
The message was emphasised that good research from New York had shown that for injectors who began injecting before 1995 the rates of HIV was substantially higher than for those who started afterwards, in just about every category of risk. New York, unlike the rest of the country, had reasonably good access to opioid maintenance treatments as well other harm reduction services such as needle “exchange”, as it is still quaintly termed here. And it largely functions in the US as just that – ‘exchange’ new for old (imagine if we did that for condoms!). We were reminded that the proportion of dependent individuals currently on opioid maintenance treatment (OMT) was calculated to have risen from 6 to 8 percent in America, showing only a modest improvement over ten years. We were reminded also that “secondary needle exchange” (pass-it-on) was vital to the success of the intervention wherein non-addicts (sometimes called ‘alcoholics’) would make small profits by returning used needles and obtaining clean supplies to be sold/distributed at a later time for money.
Dr Des Jarlais is far too experienced to lecture Americans about foreign findings yet he subtly dropped two pearls into the mix towards the end of his presentation in lower Manhattan. He had discussed and described some of the needle services here in American cities and then told the audience that (‘tiny’) New Zealand had over 600 needle exchanges while there were only about 300 in the whole of America. He alluded to the changes in federal funding for such preventive interventions but pointed out that it will take some years for such policy change to filter down to ‘street level’. In a reference to Australia our speaker also pointed out that most of the few drug injectors who contract HIV do so from sexual exposure rather than from needles (while up to 7000 Americans do so annually from contaminated needles if we are to believe the figures).
The correlation between past genital herpes simplex infection and HIV was reiterated, pointing out the behavioural and physical reasons involved. This was clarified further during question time.
While Don Des Jarlais did not quote the HIV rates in New Zealand I had done so privately with the City Health Department official Lucia Torian before she opened the session - which was delayed slightly due to new and inordinate security introduced (all visitors were photographed and ‘branded’!). She had responded to my comment that a number of countries had avoided the HIV plague, saying that I must be referring to Russia, Ukraine and North Korea where there is still denial of the existence of the epidemic in some circles. I said that in fact I was referring to Hong Kong, Australia and New Zealand. Following another off-hand remark she made, I told her that each time I mentioned this to Americans I was either disbelieved or derided, just as she was doing.
Dr Samuel Friedman acted as discussant and in half an hour elaborated some details of the presentations. He commended Dr Shardell on her study but commented that rather than only seeking views of academic experts the team might do better to include the views of knowledgeable drug users. Such folk are readily available and many have a lot to contribute. On that subject, I once asked Professor Vincent P. Dole his opinion about a new secure medicine container. He said that before giving his views he would rather hear the views of a few drug use patients.
Dr Friedman pointed out the large number of major US states and cities which no longer publish official figures on HIV cases. His personal greatest worry in epidemiology was when data was not being collected so that knowledge of the public health issues could be swept under the carpet.
Further, we were told of a study done by Dr Friedman, Des Jarlais and colleagues which showed that the different modes of transmission depending upon the infected pool involved in a given population. Where the prevalence in injectors was >20% already, some behaviours (eg. needle sharing) were directly correlated with seroconversion. Where rates of HIV were <9% risk behaviours were not statistically associated with seroconversion but rather the predictors reflected whom they injected among. We learned that the New York rate was between 9 and 20%. There was also some discussion of arrest rates, socio-economic areas and seroconversions and some research linking them.
I mentioned to Dr Des Jarlais that Hawai’i appears to have the best organised and most widespread needle availability in the US, some of which I saw on a recent visit. Dr Des Jarlais told me he was aware of that since in fact he was the official evaluator for the State’s harm reduction project! That man is everywhere! I recall that he spoke at one of the first Methadone Conferences in Sydney almost 20 years ago, warning us about the threat of HIV and the means to prevent a second wave in drug users. His advice was timely and his campaign to implement better public health strategies continues unabated. More strength to him - and his colleagues! And thanks to the New York City Health Department for sponsoring these public lectures, and allowing strays like me in.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
Opera blog: http://www.redfernclinic.com/opera/critique/blog/
New York in spring: http://ajbtravels.blogspot.com/
16 February 2010
Fatal torsade tachycardia due to methadone either rare or non-existent finds Norwegian study.
Prevalence and clinical relevance of QTc interval prolongation during methadone and buprenorphine treatment: a mortality assessment study. Anchersen K, Clausen T, Gossop M, Hansteen V, Waal H. Addiction 2009 104;6:993-999
Dear Colleagues,
This study is another high quality research paper from Scandinavia, a region which has been informing our field for decades. Because of complete citizen registers and comprehensive national health systems, such population studies can yield very meaningful results. These authors investigated the issue of QT prolongation, torsade de pointes tachycardia (TdP) and possible related cardiac mortality from two different vantage points.
One component of the study examined mortality data relating to all registered opiate maintenance treatment (OMT) patients in a seven year period to 2003 (n=2382 in 6450 years in treatment). These showed 90 deaths during the period (0.20-0.54% crude annual mortality: my own back-of-envelope calculations). Careful examination of death certificates and post mortem reports showed that only in four of the ninety could sudden cardiac death not be excluded. Thus the authors found compelling and credible non-cardiac causes of death in all but four cases. Two of the four were included purely because they did not have an autopsy performed. While there was nothing to suggest that any of these final four were in fact due to arrhythmia, the authors made a conservative calculation of the mortality as a maximum figure in the unlikely event that all were of this origin (0.06 per 100 patient years). Like most such papers, there were no reports of confirmed or suspected cases of TdP in either the death statistics or the sample of maintenance patients from Oslo. Hence the official mortality rate due to torsade de pointes was zero.
Another important finding was that there were only two deaths in the first 4 weeks from nearly 4000 ‘starts’ during the study period. One of the two was a brain haemorrhage and the other unknown causes. This is reassuring both that inductions in that country are apparently well managed and that the fear of early deaths due to TdP in predisposed individuals does not occur at a significant rate, if at all.
As the second component to their study, to re-assess prevalence of QT prolongation 200 OMT patient volunteers had an ECG performed. This group represented about 20% of the total registered OMT patients attending pharmacies and clinics in the Oslo metropolitan area. The authors state that their findings are parallel to previous studies. Buprenorphine patients had no cases of QTc > 500ms cf. 8 out of 173 (4.6%) of the methadone patients with prolonged QTc, each of them taking 120mg daily or more. They recommend ECG in those prescribed more than 120mg.
The authors state that they agree with Schmittner & Krantz (2006) in a paper entitled “QTc prolongation in methadone maintenance: fact and fiction” in which they state: “screening electrocardiography is probably unwarranted and creates a barrier to accessing care.” Anchersen and colleagues continue: “We found no evidence to suggest that the risk of QTc prolongation or TdP is especially elevated during the initial period of methadone treatment. Additionally, mortality attributable to QTc prolongation in OMT as a whole was found to be very low. We do not believe that implementation of routine ECG prior to OMT initiation would have any significant impact on mortality.”
This also casts serious doubts on the two studies of Chugh and Fanoe which both implicated TdP in fatal and non-fatal events respectively using ‘circumstantial’ methodologies. The high rates of TdP predicted by these authors are not consistent either with this Norwegian study nor have other studies provided corroboration of their deductions. Furthermore, Anchersen’s findings of low mortality in early treatment is inconsistent with Wedam’s RCT finding that prolonged QTc in early methadone treatment (>10% in their group) lead to extremely high risk of TdP in such patients. Indeed, such younger opioid dependents in early treatment seem to be almost immune from TdP considering the 100 or more reports in the literature. No cases of tachycardia were reported in any of these three studies - somthing which would also seem to confirm Anchersen’s findings.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
References:
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
Schmittner J, Krantz MJ. QTc prolongation in methadone maintenance: fact and fiction. Heroin Addict Relat Clin Probl 2006 6:41-52
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
Dear Colleagues,
This study is another high quality research paper from Scandinavia, a region which has been informing our field for decades. Because of complete citizen registers and comprehensive national health systems, such population studies can yield very meaningful results. These authors investigated the issue of QT prolongation, torsade de pointes tachycardia (TdP) and possible related cardiac mortality from two different vantage points.
One component of the study examined mortality data relating to all registered opiate maintenance treatment (OMT) patients in a seven year period to 2003 (n=2382 in 6450 years in treatment). These showed 90 deaths during the period (0.20-0.54% crude annual mortality: my own back-of-envelope calculations). Careful examination of death certificates and post mortem reports showed that only in four of the ninety could sudden cardiac death not be excluded. Thus the authors found compelling and credible non-cardiac causes of death in all but four cases. Two of the four were included purely because they did not have an autopsy performed. While there was nothing to suggest that any of these final four were in fact due to arrhythmia, the authors made a conservative calculation of the mortality as a maximum figure in the unlikely event that all were of this origin (0.06 per 100 patient years). Like most such papers, there were no reports of confirmed or suspected cases of TdP in either the death statistics or the sample of maintenance patients from Oslo. Hence the official mortality rate due to torsade de pointes was zero.
Another important finding was that there were only two deaths in the first 4 weeks from nearly 4000 ‘starts’ during the study period. One of the two was a brain haemorrhage and the other unknown causes. This is reassuring both that inductions in that country are apparently well managed and that the fear of early deaths due to TdP in predisposed individuals does not occur at a significant rate, if at all.
As the second component to their study, to re-assess prevalence of QT prolongation 200 OMT patient volunteers had an ECG performed. This group represented about 20% of the total registered OMT patients attending pharmacies and clinics in the Oslo metropolitan area. The authors state that their findings are parallel to previous studies. Buprenorphine patients had no cases of QTc > 500ms cf. 8 out of 173 (4.6%) of the methadone patients with prolonged QTc, each of them taking 120mg daily or more. They recommend ECG in those prescribed more than 120mg.
The authors state that they agree with Schmittner & Krantz (2006) in a paper entitled “QTc prolongation in methadone maintenance: fact and fiction” in which they state: “screening electrocardiography is probably unwarranted and creates a barrier to accessing care.” Anchersen and colleagues continue: “We found no evidence to suggest that the risk of QTc prolongation or TdP is especially elevated during the initial period of methadone treatment. Additionally, mortality attributable to QTc prolongation in OMT as a whole was found to be very low. We do not believe that implementation of routine ECG prior to OMT initiation would have any significant impact on mortality.”
This also casts serious doubts on the two studies of Chugh and Fanoe which both implicated TdP in fatal and non-fatal events respectively using ‘circumstantial’ methodologies. The high rates of TdP predicted by these authors are not consistent either with this Norwegian study nor have other studies provided corroboration of their deductions. Furthermore, Anchersen’s findings of low mortality in early treatment is inconsistent with Wedam’s RCT finding that prolonged QTc in early methadone treatment (>10% in their group) lead to extremely high risk of TdP in such patients. Indeed, such younger opioid dependents in early treatment seem to be almost immune from TdP considering the 100 or more reports in the literature. No cases of tachycardia were reported in any of these three studies - somthing which would also seem to confirm Anchersen’s findings.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
References:
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
Schmittner J, Krantz MJ. QTc prolongation in methadone maintenance: fact and fiction. Heroin Addict Relat Clin Probl 2006 6:41-52
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
16 November 2009
Does methadone cause QT problems or is it often viral?
HIV and Long QT syndrome - Cause or coincidence? Puri R, Roberts-Thomson KC, Young GD. International Journal of Cardiology 2009 133;1:e9-e10
Dear Colleagues,
This may be the first article to formally describe the link between HIV and torsade de pointes tachycardia and at the same time to question the role of methadone. Their single case report has much in common with others in the literature: the 36 year old female with HIV was taking long term methadone for dependency and presented with recurrent syncope. The dose was only 70mg daily at the time of the torsade but importantly, had been 190mg daily 18 months previously – at which time ECG showed the QTc to be normal - and there were no cardiac symptoms. The authors proposed that their patient did not have methadone induced QT changes, but HIV-induced long QT (LQT) syndrome. The QTc was 540ms around the time of the torsade.
These authors go on to discuss the effects of HIV on the heart. Up to 60% apparently have positive cardiac findings at autopsy and 30% of cases may have asymptomatic prolonged QTc, largely in the absence of ‘culprit’ medications (citing Kocheril 1997). “Minor repolarisation abnormalities in HIV infecteds may therefore become clinically overt in the setting of concomitant predisposing drug therapies.”
The authors state in their introduction: “Methadone use has been associated with prolongation of the QTc and an increased risk of sudden cardiac death.” In fact after 40 years of widespread use there has been no such association with sudden cardiac deaths. Yet this statement well exemplifies the current popular mythology around the subject. Since Krantz and colleagues wrote the original case series (but not the first case) in 2002, there have been no confirmed or strongly suspected deaths due to torsade tachycardia from my reading. The only 2 or 3 deaths were either remote from the period of the torsade and/or else were due to another reported cause such as myocardial infarction. French reports from over 30 years ago quote a mortality from ‘torsade de pointes’ of around 16%. Since this was before modern mobile resuscitation and pacing technologies were widespread, the survival rate of 84% might have increased to something over 95%.
It is now clear that ‘torsade de pointes’ tachycardia rarely if ever occurs in new entrants to methadone treatment. The 103 reports in the literature and Justo’s excellent summary of the field in the Addiction journal inform us that simple clinical features can highlight risk and indicate the need for ECG monitoring where appropriate. Almost 50% of the ~100 reported cases in the literature had HIV infection. The author of the original FDA report, Ellen Pearson, has postulated that QT prolongation and torsade are ‘threshold events’ with numerous contributors based on the known risk factors.
The risk factors (not in order) are:
(1) long term methadone maintenance for addiction
(2) female sex
(3) age over 40
(4) doses over 150mg daily
(5) HIV infection
(6) concomitant use of drugs which either increase methadone levels and/or prolong QT interval
(7) metabolic disturbance
(8) structural heart disease
(9) alcohol
When used with supervision and adequate supports methadone treatment for heroin addiction reduces mortality substantially. It should be used with confidence as the benefits far outweigh even the most pessimistic views of the possible side effects.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
Refs:
Kocheril AG, Bokhari SAJ, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997 20:2810-6
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
Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72
Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Safety. 2005 14;11:747-753
Dear Colleagues,
This may be the first article to formally describe the link between HIV and torsade de pointes tachycardia and at the same time to question the role of methadone. Their single case report has much in common with others in the literature: the 36 year old female with HIV was taking long term methadone for dependency and presented with recurrent syncope. The dose was only 70mg daily at the time of the torsade but importantly, had been 190mg daily 18 months previously – at which time ECG showed the QTc to be normal - and there were no cardiac symptoms. The authors proposed that their patient did not have methadone induced QT changes, but HIV-induced long QT (LQT) syndrome. The QTc was 540ms around the time of the torsade.
These authors go on to discuss the effects of HIV on the heart. Up to 60% apparently have positive cardiac findings at autopsy and 30% of cases may have asymptomatic prolonged QTc, largely in the absence of ‘culprit’ medications (citing Kocheril 1997). “Minor repolarisation abnormalities in HIV infecteds may therefore become clinically overt in the setting of concomitant predisposing drug therapies.”
The authors state in their introduction: “Methadone use has been associated with prolongation of the QTc and an increased risk of sudden cardiac death.” In fact after 40 years of widespread use there has been no such association with sudden cardiac deaths. Yet this statement well exemplifies the current popular mythology around the subject. Since Krantz and colleagues wrote the original case series (but not the first case) in 2002, there have been no confirmed or strongly suspected deaths due to torsade tachycardia from my reading. The only 2 or 3 deaths were either remote from the period of the torsade and/or else were due to another reported cause such as myocardial infarction. French reports from over 30 years ago quote a mortality from ‘torsade de pointes’ of around 16%. Since this was before modern mobile resuscitation and pacing technologies were widespread, the survival rate of 84% might have increased to something over 95%.
It is now clear that ‘torsade de pointes’ tachycardia rarely if ever occurs in new entrants to methadone treatment. The 103 reports in the literature and Justo’s excellent summary of the field in the Addiction journal inform us that simple clinical features can highlight risk and indicate the need for ECG monitoring where appropriate. Almost 50% of the ~100 reported cases in the literature had HIV infection. The author of the original FDA report, Ellen Pearson, has postulated that QT prolongation and torsade are ‘threshold events’ with numerous contributors based on the known risk factors.
The risk factors (not in order) are:
(1) long term methadone maintenance for addiction
(2) female sex
(3) age over 40
(4) doses over 150mg daily
(5) HIV infection
(6) concomitant use of drugs which either increase methadone levels and/or prolong QT interval
(7) metabolic disturbance
(8) structural heart disease
(9) alcohol
When used with supervision and adequate supports methadone treatment for heroin addiction reduces mortality substantially. It should be used with confidence as the benefits far outweigh even the most pessimistic views of the possible side effects.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
Refs:
Kocheril AG, Bokhari SAJ, Batsford WP, et al. Long QTc and torsades de pointes in human immunodeficiency virus disease. Pacing Clin Electrophysiol 1997 20:2810-6
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
Dessertenne PF. La tachycardie ventriculaire a deux foyers opposes variables. Arch Mal Coeur 1966 59:263-72
Pearson EC, Woosley RL. QT prolongation and torsades de pointes among methadone users: reports to the FDA spontaneous reporting system. Pharmcoepidemiol Drug Safety. 2005 14;11:747-753
Methadone safe in cancer patients - minor QT problems went away after 4-8 weeks methadone
The Effect of Oral Methadone on the QTc Interval in Advanced Cancer Patients: A Prospective Pilot Study. Reddy S, Hui D, El Osta B, de la Cruz M, Walker M, Palmer JL, Bruera E. Journal of Palliative Medicine, October 13, 2009 E-pub ahead.
Dear Colleagues,
These authors have done a great service by following serial ECGs prospectively on 100 patients who were being considered for methadone treatment for advanced cancer pain. ECG was ordered at baseline, 2, 4 and 8 weeks. Due to altered medication, hospice transfers, community discharges and one death (non-cardiac) in this palliative patient population the follow up results were available for 64, 41, and 27 patients at 2, 4 and 8 weeks.
Perhaps the most interesting and unexpected findings of this study were that even before starting the medication, over a quarter of patients (28%) had QT prolongation (>430 ms in males; >450 ms in females) and this dropped. The proportion of subjects was *lower* at each of the follow-up periods with only 8-11% of patients having QT prolongation.
At two weeks 11 patients (17%) had QTc>10% above baseline. However, by 4 and 8 weeks this had dropped to one single patient (3%). There was only one ECG in one single patient where QTc increased beyond 500ms (1.6%). This was asymptomatic and not associated with any tachycardia episode. Furthermore, that patient’s prolonged QT resolved spontaneously in subsequent ECG tracings. The authors express their surprise at these unexpected findings which they ascribed partly to the high baseline occurrence of QT prolongation and/or possibly a reduction in other drugs prescribed or improvements in electrolyte disturbances.
The doses of methadone were relatively low compared to the dose levels used for addiction (median at 2 weeks 23mg daily and maximum was 90mg daily).
The authors conclude: “clinically significant QTc prolongation rarely occurred … our preliminary findings are encouraging. … we believe that methadone should be prescribed without reservations … . For patients with significant risk factors … monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”
This should give doctors and patients confidence that methadone is still a safe and effective analgesic and that concerns regarding cardiac side effects may have been exaggerated out of keeping with the literature. When I contacted the study’s author I was told that they had seen no cases of torsade tachycardia in relation to methadone treatment at the MD Anderson Cancer Center to date.
Comments by Andrew Byrne ..
Dear Colleagues,
These authors have done a great service by following serial ECGs prospectively on 100 patients who were being considered for methadone treatment for advanced cancer pain. ECG was ordered at baseline, 2, 4 and 8 weeks. Due to altered medication, hospice transfers, community discharges and one death (non-cardiac) in this palliative patient population the follow up results were available for 64, 41, and 27 patients at 2, 4 and 8 weeks.
Perhaps the most interesting and unexpected findings of this study were that even before starting the medication, over a quarter of patients (28%) had QT prolongation (>430 ms in males; >450 ms in females) and this dropped. The proportion of subjects was *lower* at each of the follow-up periods with only 8-11% of patients having QT prolongation.
At two weeks 11 patients (17%) had QTc>10% above baseline. However, by 4 and 8 weeks this had dropped to one single patient (3%). There was only one ECG in one single patient where QTc increased beyond 500ms (1.6%). This was asymptomatic and not associated with any tachycardia episode. Furthermore, that patient’s prolonged QT resolved spontaneously in subsequent ECG tracings. The authors express their surprise at these unexpected findings which they ascribed partly to the high baseline occurrence of QT prolongation and/or possibly a reduction in other drugs prescribed or improvements in electrolyte disturbances.
The doses of methadone were relatively low compared to the dose levels used for addiction (median at 2 weeks 23mg daily and maximum was 90mg daily).
The authors conclude: “clinically significant QTc prolongation rarely occurred … our preliminary findings are encouraging. … we believe that methadone should be prescribed without reservations … . For patients with significant risk factors … monitoring with ECGs at baseline and at subsequent intervals may be reasonable.”
This should give doctors and patients confidence that methadone is still a safe and effective analgesic and that concerns regarding cardiac side effects may have been exaggerated out of keeping with the literature. When I contacted the study’s author I was told that they had seen no cases of torsade tachycardia in relation to methadone treatment at the MD Anderson Cancer Center to date.
Comments by Andrew Byrne ..
1 November 2009
Safe and effective opioid prescribing in addiction treatment. Article written for UK psychiatry journal.
Commissioned by editor of 'Advances in Psychiatric Treatment', accepted, paid for but never published for reasons quoted as relating to 'legal matters'.
Safe and effective opioid prescribing in addiction treatment.
Author Dr Andrew Byrne
Abstract:
A large body of research supports the prescribing of maintenance opioids for heroin addiction yet poor quality treatment in the UK has limited the potential benefits. This in turn has caused many to become disillusioned about addiction treatment generally. Inadequate dose levels without the necessary supervision and psychosocial supports have both contributed to this state of affairs in the UK. By failing to address this situation, the National Addiction Centre in London has actually perpetuated it. While some progress has been made in recent years, psychiatry trainees in the UK are ideally placed to help improve the quality of pharmacotherapies in line with other European countries in moving towards an evidence base.
Article:
The principles linking opioid maintenance treatment and behavioural therapies were defined in Dole and Nyswander’s classic paper which is now one of the most quoted in the medical literature [ref 1]. Psychiatrist Marie Nyswander had noted limited success treating heroin addicts in New York using psychoanalytic techniques alone. With Dr Dole, she reported a cohort of ‘hopeless’ New York street addicts responding favourably to a trial of strictly supervised, ‘high-dose’ methadone treatment (mean 100mg/d, range 15-180) with intensive psychosocial supports. They found dramatic reductions in illicit drugs use, excellent retention in treatment along with vocational, social and other demographic improvements. The trial was radical at the time as it placed social functioning as its primary goal, rather than abstinence from all opiates. Patients received daily supervised medication and their drug use was monitored by regular urine tests as part of treatment. Many rigorous studies since have further refined ‘best practice’ and also documented safety data. These were especially important in long-term patients, pregnancy and in those with coexisting mental illness.
Over four succeeding decades, methadone and other maintenance treatments have become just one component of a more complex therapeutic repertoire for addiction including the anti-craving drugs, mood altering medications, detoxification, brief interventions, CBT, formal psychotherapy and other strategies. These are all aimed primarily at reducing the harms from drug addiction while also encouraging engagement in normal social activities. Contrary to popular opinion, the natural history of opiate use, like smoking and alcoholism, in fact moves towards abstinence, with or without treatment [ref 2].
British perspective – historical background of opioid treatment in the UK.
Due to an unwillingness of the dependency establishment to accept methadone as a valid maintenance treatment, a majority of heroin users in treatment in the UK have been subjected to a ‘culture of abstinence’. This is akin to Nancy Reagan’s retort of “just say no to drugs!” Like smokers, drug addicts are generally well aware of the dangers they are taking. Even by 1989 when methadone maintenance was being introduced into many other countries, UK treatment practise was only for short term reduction prescribing. We knew then as now that this leads to relapse in over 90% of cases.
At a time when needle sharing was still common, this caused many otherwise preventable cases of HIV. To this day, many doctors in the UK will only condone short-term, low dose methadone. Others continue to implement a punitive policy of enforced dose reductions when drug use, even non-opiate drug use, is found on urine testing. Some NHS clinics refuse to readmit their own old discharged patients for arbitrary periods, raising further barriers for those most needing assistance.
In the 1980s two forward thinking doctors introduced a more evidence based type of maintenance treatment into Scotland using GP ‘shared care’. Pharmacists were instructed (and paid) to witness the administration of liquid doses and an emphasis on rehabilitation replaced a priority of dose reductions to abstinence [ref 3]. High quality, clinic-based services were also developed in some centres in England (eg. Sheffield, Portsmouth, Manchester). Nevertheless, a large proportion of methadone in the UK was still prescribed ‘on demand’ in general practice using doses which were often inadequate and ineffective, and in settings where there was no dose supervision, little urine testing and no check on compliance. The poor outcomes led predictably to a cycle of negative attitudes towards methadone treatment which persists to the present day [ref 4]. With the unrealistic goal of short term abstinence, it is not surprising that many informed citizens, parents, police and even health workers held little confidence in methadone treatment, despite its glowing record in public health circles when properly implemented.
Uniquely in the UK, methadone and other opioid prescriptions are at least theoretically available to all addicts through the NHS. This would utilise GPs and/or specialist clinics with other health workers giving counselling and psycho-social supports which are known to improve outcomes [ref 5]. Pharmacists or clinic nurses would administer (supervised doses) and dispense (give out medication for later consumption) the medication. Guidelines were finally introduced in 1999 which incorporated what Dole in New York and others around the world had been doing for decades [ref 6]. These advised maintenance treatment and also the use of supervised dosing for new and unstable patients as well as adequate dose schedules. Yet even four years later Strang et al report that most methadone is given without supervision and in doses which are still inadequate for most to curtail injecting behaviour [ref 7].
Some jurisdictions which introduced methadone maintenance propitiously have avoided the HIV epidemic almost completely in their injecting population (Hong Kong, Australia, New Zealand). Unfortunately, for reasons which are still being elucidated, this did not extend to hepatitis C which continues to spread even where new HIV cases had almost ceased.
What is opioid maintenance treatment? What can it do? What can’t it do?
Who needs treatment? When do they need it? The first dose.
Who is best placed to provide such treatments?
So what is needed for the future?
What is opioid maintenance treatment? What can it do? What can’t it do?
Opioid maintenance treatment involves the legal prescribing of a drug of dependence to an addicted patient within a defined therapeutic framework, involving goals, support, supervision and regular review. Short term opioid abstinence is usually considered secondary to other goals such as reduced risk taking behaviour, better general health, work, education and family responsibilities.
Many things change in an addict’s life when starting opioid maintenance treatment. Studies have shown mortality declines from over 2% per years to less than 0.5% [refs 8,9]. Since there is less injecting, viral disease is less likely to be passed on by those who are already infected. As well as less injecting, employment, legal and financial matters have all been shown to improve substantially for those in treatment (Ref 9b). And the longer treatment lasts, the greater these improvements. This is not to say that everyone needs treatment indefinitely and a large proportion do successfully withdraw from maintenance opioids [refs 2, 12].
Only a very small proportion of patients will successfully withdraw from the opioid treatment in the short term and still remain opiate abstinent [ref 9b]. This is probably less than 10% of the total, even though many more express a desire for such an outcome. Hence all opioid dependent patients should have access to continuing prescribed opioids and those who discontinue should be encouraged to seek supports which seem appropriate for the individual.
Who needs treatment? When do they need it? The first dose.
A careful assessment is essential in any patient presenting with drug or alcohol problems. This involves a thorough history, physical examination (pupils, mental state and injecting sites as a minimum) and usually a supervised urine test and blood tests including liver function, hepatitis B/C, HIV status, etc. As for other medical prescribing, the necessary minimum includes both a clear diagnosis and, usually, the failure of non-drug treatments. In practice, the need for opioid maintenance is relatively easy to establish, except in the very young or in those with concurrent medical or psychiatric illness. The diagnostic criteria for opiate dependence involve compulsive self administration, escalating doses, withdrawal effects and usually, documented adverse health and social consequences. It is important to document all of these clearly in the patient record before prescribing any medication. In addition, the patient’s identity and some aspects of their past treatment history needs to be confirmed.
To make our job easier, patients may have ‘self-selected’ by seeking out a doctor or clinic where dependency services are available. Some may not want methadone but seek other medications to assist with detoxification. Such patients should be informed of the benefits of maintenance therapies in case their detox episode is unsuccessful. All patients should be informed about self help groups including AA, NA and the new SMART Recovery movement [ref 10].
Most patients will have a substantial history of heroin or other opioid use, often by injection and with documented complications, end-organ damage, legal, financial and social consequences. Venous scarring is the most obvious sign of long term history. The drug use may take the form of injected heroin, black market methadone, codeine, morphine, opium or even poppy seeds in rare cases. As long as the use is consistent and compulsive with tolerance and withdrawal symptoms/signs the criteria of dependency are fulfilled. It is helpful to use the DSM-IV definition although it must be remembered that this was devised for use by private American psychiatrists and there may be occasional deviations in ‘normal’ countries.
In patients who are very young (under 18 years) or who have unstable mental illness, it is important to ascertain that opiate opioid maintenance therapy is indeed the most suitable option at the time. Some such patients may develop a mistaken notion that they need prescribed opiates opioids. They may also give a credible history of dependence. This always needs to be carefully corroborated with physical examination and urine testing. This is especially so if there are no venipunctures, no history of hepatitis C, overdose, financial, legal or other consequences of opiate dependence. In such sensitive cases it is prudent to seek a written opinion from a colleague to ensure that other forms of treatment may not be more appropriate. This may be the patient’s own GP or consultant who has been involved. In some jurisdictions parental permission may be required at this age. Health authorities or family services may also have to be involved in under-age cases, with details varying between jurisdictions.
As with other major treatment decisions, the patient should fully informed about its nature. This essential information should be given verbally, allowing for questions, as well as in writing. Various documents are available on the internet for patient education. Some documentation of consent should also be obtained in the patient records. Patients need to know that both methadone and buprenorphine have benefits and also certain side effects such as headache, constipation and sweating. The issue of cardiac conduction defects has never been shown to be a problem in patients being treated under dependency guidelines. However, for those taking higher doses (>150mg daily) or with other risk factors a cardiograph is a prudent step [ref 11].
Although many patients do attain opiate abstinence, methadone and buprenorphine treatments are not ‘cures’ for addiction. Patients should be aware that this is a treatment which requires regular attendance for medication, medical reviews, counselling and urine testing. They should also be informed that this treatment often lasts for months and sometimes for years. The myth of methadone being “for life” has been disproved by longitudinal studies with acronyms NTORS, ATOS, etc [ref 12]. Gossop points out that because clinics see successful patients less often than others, staff may develop the incorrect impression that few ever successfully withdraw from treatment.
Patients often arrive in distress and dismay, wanting to get into treatment urgently. It is still essential to ascertain who needs opioids and who may be more appropriate for detoxification services. Just because a patient says that they are in withdrawals does not mean that a doctor must write a prescription for opioids, although this should always be seriously considered as an option. Prescribing always has more predictable outcomes than detoxification. The doctor takes responsibility for the former and the patient the latter. Vincent Dole, the co-inventor of methadone treatment, said that “detoxification is an experiment in the life of the patient”
Who is best to provide such treatments? How is it done?
The delivery of methadone can occur in either the specialised clinic setting or in existing community facilities. There are advantages and disadvantages to both types, but ideally, new and unstable addiction cases would be treated in a specialised clinic. This allows close supervision for a period, after which stable and longer term patients could be referred back to GPs and pharmacists for community treatment. In practice there are usually more patients than services available so any treatment opportunity will have immediate applicants, most of whom are assessed as appropriate for maintenance treatment.
As with other acute presentations, one cannot do everything in the first consultation. However the basics need to be organized and a decision taken promptly as to whether or not the patient is to be prescribed opioids in a treatment ‘program’. At that point, one can afford to put off certain other matters until the patient feels better and has more confidence and familiarity with the staff and treatment setting. Another essential detail at this point is whether the patient has adequate housing considering they may be dispensed bottles of strong medicine. Also one needs to find out if there are children in the house and stress the importance of safe drug storage out of their reach.
The first dose.
The patient should usually be given a starting dose of 30mg with small increases in subsequent days up to the usual effective dose of 60 – 120mg. If given too quickly, drug accumulation can cause fatal toxicity so vigilance is needed in the first two weeks when this can occur. An additional 5 to 10mg every 2 to 3 days is usually a safe increase. On the other hand, if doses are kept too low, some patients will drop out while others may continue to use street drugs and/or alcohol. In some clinical settings it may be possible to give supplementary doses later the same day but only if the prescribing doctor has examined the patient 2 to 4 hours after the first dose. Where supplements are given, the second day’s dose should normally be the sum of the first day’s doses as long as there is no sign of toxicity.
Inductions onto buprenorphine are not as critical since early overdose is not a problem owing to the “ceiling effect” for respiratory depression. Most start with 4 to 8mg as a supervised sublingual dose, increasing only after 3 to 4 days when steady-state levels are achieved in this very long acting drug. Supplements may also be given, but these should be considered ‘loading doses’ and may only be needed in the first few days. The usual effective dose is 6 to 16mg daily with only a small proportion requiring more or less than this level. 32mg is the maximum daily dose.
Patients often know from previous experience how much they need and which drug suits them best. About a third of heroin addicts treated with buprenorphine will continue to feel drug cravings even when doses have been raised to the maximum of 32mg daily [ref 13]. Such patients usually do well on methadone using standard doses. For this and other reasons, methadone is probably still the best first line drug. A smaller proportion of methadone patients report unacceptable side effects such as sedation, sexual dysfunction, constipation or sweating and a transfer to buprenorphine can be very rewarding. However this can only be done ideally when the methadone dose has been reduced below 40mg daily due to the potential for a precipitated withdrawal episode as the partial opioid agonist buprenorphine replaces the full agonist methadone. This can be very unpleasant although it is usually short lived, in most cases less than one hour.
The first month of treatment is crucial to long term success. Hence it is essential to engage with the patient and establish a confident and professional relationship. This will involve all health care workers from reception staff to nursing, medical and pharmacists.
As with other conditions, management involves educating our patients, prescribing medications judiciously and supervising and monitoring progress. As with diabetes, depression or blood pressure, there is wide variation in views about how frequently patients may need to see a doctor, counsellor, pathology service or pharmacist. But the general principle is that new and unstable patients need more frequent and intensive involvement than long-term stable patients. Where there are psychologists, counsellors and other staff medical visits may be less frequent after the first month of treatment. There should be a formal interview each week until the patient shows signs of stability, then 2 to 4 weekly consultations should suffice for a year. Even very long term patients should probably see their prescriber every two months at a minimum.
Urine testing.
All patients who have come to the attention of dependency services should probably have urine testing at some frequency. This is essential at the initial assessment and twice yearly urine toxicology is probably a minimum for any person prescribed take-home doses of opioids, probably including pain management cases. Tests should be ‘supervised’ to some degree. The most useful tests for research or legal purposes will be directly witnessed and done at random. This is not always practical, nor is it necessary in most cases in clinical practice, unless the patient needs to prove their status for legal, family, sporting or sensitive employment matters. It is usually sufficient to ask for a urine test on a particular consultation day and have the staff test the temperature of the specimen. This may be done manually or using adherent temperature sensitive strips.
The interpretation of urine testing involves distinguishing non-specific ‘opiate’ positive tests from ‘morphine’ which is the breakdown product of heroin. One must take into account the half-lives of the cannabinoids, benzodiazepines, cocaine, amphetamine, etcetera. There should be no punitive outcomes from urine tests and these should only be used as a clinical indicator.
Dose supervision.
For new and unstable patients, as with other areas of medical practice, outcomes are directly related to compliance. The treatment of malaria, TB and HIV have each been shown to improve with directly observed treatment [refs 14,15]. Likewise with opioid therapies, witnessed doses improve outcomes and reduce the scope for diversion. In practice, most patients can be successfully treated by attending one to three times weekly depending on time in treatment, stability and dose level. The uniquely British practice of attendance at the pharmacy every one of two days to take bottles of medicine home is not based on any research and should be abandoned.
Cardinal rules for methadone:
The effective dose is generally 60-120mg daily with a small proportion needing more or less that this range due to unusual metabolism or tolerance. No more than 30mg should be given as a starting dose with increases of 5-10mg every 2-3 days, more rapidly only where close medical supervision is possible. Methadone should be avoided with fluvoxamine (inhibits metabolism), phenytoin or carbamazepine (induce metabolism) or pentazocine (may precipitate withdrawal, like buprenorphine). Special precautions are also necessary with various anti-HIV and TB drugs which may increase or decrease blood levels of methadone. Even grapefruit juice, with its effect on the cytochrome P450 enzymes can reduce methadone metabolism and raise levels. The principle is to carefully monitor any patient who is prescribed other drugs and be prepared to raise or lower the dose as appropriate – an examination 3-4 hours post-dose for signs of intoxication, and 24 hours afterwards for signs of withdrawal is generally more useful than measuring methadone blood levels [ref 16]. Patients should be warned not to drive, operate machinery or look after children until they are stable.
So what is needed for the future?
Treating addictions can be enormously rewarding and one does not have to wait for years to see the fruits of interventions. Many of these patients are ‘survivors’ who have enormous energy and resources which they often use to turn their lives around while in treatment. A ‘lapse’ back to drug use does not imply failure, but may mean that more attention needs to be paid to treatment. In cases of ‘relapse’, a second attempt at treatment is more likely to be successful than the first, especially if depression and anxiety are correctly dealt with.
All psychiatrists should be comfortable with treating dependency problems. There are some parallels between the management of nicotine, alcohol, opiate and stimulant addictions. Each has a behavioural and a chemical component. We should be aware of the differences and the similarities, each requiring appropriate interventions when required. Addictions are still inadequately covered in most undergraduate and family medicine training. Indeed, there was a time when some considered substance dependency not to be an area for doctors, nurses and pharmacists at all!
It is essential that consultant psychiatrists know how to set up and run a dependency unit within a community hospital setting. These will have the ability to take referrals with a view to assessments and a range of treatments, both medicated and non-medicated, based on rational, practical and cost-effective principles. As with general psychiatry, the great majority of such cases can be handled as out-patients but a small sub-set will need hospital admission. As with alcoholism, needs may vary from just brief respite care to acute care and intensive treatment. All the same principles of good medical practice should apply just as in every other medical specialty. While in treatment special attention needs to be paid to other areas of risk such as hepatitis C and other communicable diseases [ref 17].
Opioid maintenance treatment should be considered for all those who are addicted to either street heroin or pharmaceutical opioids and who are unable or unwilling to cease using such drugs. The same could be said for nicotine or, indeed, many medical situations where prescribing is only appropriate when non-drug approaches have failed or are inappropriate (eg. diabetes, hypertension, hyperlipidaemia).
For reasons which would be unacceptable in other fields, deficiencies in dependency treatments in the UK have undoubtedly contributed to the epidemics of HIV, hepatitis C, overdose and other consequences of addiction. It may take many years to turn these deficiencies around. Conceding them would be a great starting point. Methadone treatment has long been treated with great suspicion by the addiction ‘establishment’ in the UK. Indeed, Professor John Strang of the Maudsley Hospital has revealed his own misgivings about methadone by claiming that, despite its known benefits, it may have a ‘bitter final pathological twist’ (ref 18). Such personal reservations stand in stark contrast to 40 years of positive research findings, much published in the high rating journal, Addiction, of which he is an assistant editor.
References:
1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50
2. Thorley A. Longitudinal Studies of Drug Dependence. In: Drug Problems in Britain: A review of ten years. Eds: Edwards G, Busch C. 1981, Academic Press. p162
3. Greenwood J. Six years' experience of sharing the care of Edinburgh's drug users. Psychiatric Bulletin 1996 20:8-11
4. Stevenson RJ. Drug misusers are likely to abuse the system. BMJ 2007 335:317
5. McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The Effects of Psychosocial Services in Substance Abuse Treatment. JAMA 1993 269:1953-1959.
6. Drug Misuse and Dependence - Guidelines on Clinical Management. 1999 HMSO Department of Health. Working Group Chair: Strang J.
7. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice 2005 55;515:444-451
8. Caplehorn JRM, Dalton MSYN, Cluff MC, Petrenas A. Retention in methadone maintenance and heroin addicts' risk of death. Addiction 1994 89:203-7
9. Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990 82:223-227
9b Gossop M, Marsden J, Stewart D, Treacy S. Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study. Drug and Alcohol Dep 2001 62;3:255-264
10. Self management and Recovery Training. http://www.smartrecovery.co.uk/ (accessed on 13/2/08).
11. Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366
12. Gossop M. The clinical fallacy and treatment outcomes. Addiction 2007 103:89
13. Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück 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
14. Babudieri S, Aceti A, D'Offizi GP, Carbonara S, Starnini G. Directly Observed Therapy to Treat HIV Infection in Prisoners. JAMA 2000 284;2:179-180
15. Garner P, Volmink J. Directly observed treatment for tuberculosis. BMJ 2003 327:823-824
16. 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
17. 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
18. Strang J. Looking beyond death: paying attention to other important consequences of heroin overdose. Addiction 2002 97:927-928
Declaration of interest:
Dr Byrne’s addiction clinic charges a fee for dispensing methadone and buprenorphine.
Safe and effective opioid prescribing in addiction treatment.
Author Dr Andrew Byrne
Abstract:
A large body of research supports the prescribing of maintenance opioids for heroin addiction yet poor quality treatment in the UK has limited the potential benefits. This in turn has caused many to become disillusioned about addiction treatment generally. Inadequate dose levels without the necessary supervision and psychosocial supports have both contributed to this state of affairs in the UK. By failing to address this situation, the National Addiction Centre in London has actually perpetuated it. While some progress has been made in recent years, psychiatry trainees in the UK are ideally placed to help improve the quality of pharmacotherapies in line with other European countries in moving towards an evidence base.
Article:
The principles linking opioid maintenance treatment and behavioural therapies were defined in Dole and Nyswander’s classic paper which is now one of the most quoted in the medical literature [ref 1]. Psychiatrist Marie Nyswander had noted limited success treating heroin addicts in New York using psychoanalytic techniques alone. With Dr Dole, she reported a cohort of ‘hopeless’ New York street addicts responding favourably to a trial of strictly supervised, ‘high-dose’ methadone treatment (mean 100mg/d, range 15-180) with intensive psychosocial supports. They found dramatic reductions in illicit drugs use, excellent retention in treatment along with vocational, social and other demographic improvements. The trial was radical at the time as it placed social functioning as its primary goal, rather than abstinence from all opiates. Patients received daily supervised medication and their drug use was monitored by regular urine tests as part of treatment. Many rigorous studies since have further refined ‘best practice’ and also documented safety data. These were especially important in long-term patients, pregnancy and in those with coexisting mental illness.
Over four succeeding decades, methadone and other maintenance treatments have become just one component of a more complex therapeutic repertoire for addiction including the anti-craving drugs, mood altering medications, detoxification, brief interventions, CBT, formal psychotherapy and other strategies. These are all aimed primarily at reducing the harms from drug addiction while also encouraging engagement in normal social activities. Contrary to popular opinion, the natural history of opiate use, like smoking and alcoholism, in fact moves towards abstinence, with or without treatment [ref 2].
British perspective – historical background of opioid treatment in the UK.
Due to an unwillingness of the dependency establishment to accept methadone as a valid maintenance treatment, a majority of heroin users in treatment in the UK have been subjected to a ‘culture of abstinence’. This is akin to Nancy Reagan’s retort of “just say no to drugs!” Like smokers, drug addicts are generally well aware of the dangers they are taking. Even by 1989 when methadone maintenance was being introduced into many other countries, UK treatment practise was only for short term reduction prescribing. We knew then as now that this leads to relapse in over 90% of cases.
At a time when needle sharing was still common, this caused many otherwise preventable cases of HIV. To this day, many doctors in the UK will only condone short-term, low dose methadone. Others continue to implement a punitive policy of enforced dose reductions when drug use, even non-opiate drug use, is found on urine testing. Some NHS clinics refuse to readmit their own old discharged patients for arbitrary periods, raising further barriers for those most needing assistance.
In the 1980s two forward thinking doctors introduced a more evidence based type of maintenance treatment into Scotland using GP ‘shared care’. Pharmacists were instructed (and paid) to witness the administration of liquid doses and an emphasis on rehabilitation replaced a priority of dose reductions to abstinence [ref 3]. High quality, clinic-based services were also developed in some centres in England (eg. Sheffield, Portsmouth, Manchester). Nevertheless, a large proportion of methadone in the UK was still prescribed ‘on demand’ in general practice using doses which were often inadequate and ineffective, and in settings where there was no dose supervision, little urine testing and no check on compliance. The poor outcomes led predictably to a cycle of negative attitudes towards methadone treatment which persists to the present day [ref 4]. With the unrealistic goal of short term abstinence, it is not surprising that many informed citizens, parents, police and even health workers held little confidence in methadone treatment, despite its glowing record in public health circles when properly implemented.
Uniquely in the UK, methadone and other opioid prescriptions are at least theoretically available to all addicts through the NHS. This would utilise GPs and/or specialist clinics with other health workers giving counselling and psycho-social supports which are known to improve outcomes [ref 5]. Pharmacists or clinic nurses would administer (supervised doses) and dispense (give out medication for later consumption) the medication. Guidelines were finally introduced in 1999 which incorporated what Dole in New York and others around the world had been doing for decades [ref 6]. These advised maintenance treatment and also the use of supervised dosing for new and unstable patients as well as adequate dose schedules. Yet even four years later Strang et al report that most methadone is given without supervision and in doses which are still inadequate for most to curtail injecting behaviour [ref 7].
Some jurisdictions which introduced methadone maintenance propitiously have avoided the HIV epidemic almost completely in their injecting population (Hong Kong, Australia, New Zealand). Unfortunately, for reasons which are still being elucidated, this did not extend to hepatitis C which continues to spread even where new HIV cases had almost ceased.
What is opioid maintenance treatment? What can it do? What can’t it do?
Who needs treatment? When do they need it? The first dose.
Who is best placed to provide such treatments?
So what is needed for the future?
What is opioid maintenance treatment? What can it do? What can’t it do?
Opioid maintenance treatment involves the legal prescribing of a drug of dependence to an addicted patient within a defined therapeutic framework, involving goals, support, supervision and regular review. Short term opioid abstinence is usually considered secondary to other goals such as reduced risk taking behaviour, better general health, work, education and family responsibilities.
Many things change in an addict’s life when starting opioid maintenance treatment. Studies have shown mortality declines from over 2% per years to less than 0.5% [refs 8,9]. Since there is less injecting, viral disease is less likely to be passed on by those who are already infected. As well as less injecting, employment, legal and financial matters have all been shown to improve substantially for those in treatment (Ref 9b). And the longer treatment lasts, the greater these improvements. This is not to say that everyone needs treatment indefinitely and a large proportion do successfully withdraw from maintenance opioids [refs 2, 12].
Only a very small proportion of patients will successfully withdraw from the opioid treatment in the short term and still remain opiate abstinent [ref 9b]. This is probably less than 10% of the total, even though many more express a desire for such an outcome. Hence all opioid dependent patients should have access to continuing prescribed opioids and those who discontinue should be encouraged to seek supports which seem appropriate for the individual.
Who needs treatment? When do they need it? The first dose.
A careful assessment is essential in any patient presenting with drug or alcohol problems. This involves a thorough history, physical examination (pupils, mental state and injecting sites as a minimum) and usually a supervised urine test and blood tests including liver function, hepatitis B/C, HIV status, etc. As for other medical prescribing, the necessary minimum includes both a clear diagnosis and, usually, the failure of non-drug treatments. In practice, the need for opioid maintenance is relatively easy to establish, except in the very young or in those with concurrent medical or psychiatric illness. The diagnostic criteria for opiate dependence involve compulsive self administration, escalating doses, withdrawal effects and usually, documented adverse health and social consequences. It is important to document all of these clearly in the patient record before prescribing any medication. In addition, the patient’s identity and some aspects of their past treatment history needs to be confirmed.
To make our job easier, patients may have ‘self-selected’ by seeking out a doctor or clinic where dependency services are available. Some may not want methadone but seek other medications to assist with detoxification. Such patients should be informed of the benefits of maintenance therapies in case their detox episode is unsuccessful. All patients should be informed about self help groups including AA, NA and the new SMART Recovery movement [ref 10].
Most patients will have a substantial history of heroin or other opioid use, often by injection and with documented complications, end-organ damage, legal, financial and social consequences. Venous scarring is the most obvious sign of long term history. The drug use may take the form of injected heroin, black market methadone, codeine, morphine, opium or even poppy seeds in rare cases. As long as the use is consistent and compulsive with tolerance and withdrawal symptoms/signs the criteria of dependency are fulfilled. It is helpful to use the DSM-IV definition although it must be remembered that this was devised for use by private American psychiatrists and there may be occasional deviations in ‘normal’ countries.
In patients who are very young (under 18 years) or who have unstable mental illness, it is important to ascertain that opiate opioid maintenance therapy is indeed the most suitable option at the time. Some such patients may develop a mistaken notion that they need prescribed opiates opioids. They may also give a credible history of dependence. This always needs to be carefully corroborated with physical examination and urine testing. This is especially so if there are no venipunctures, no history of hepatitis C, overdose, financial, legal or other consequences of opiate dependence. In such sensitive cases it is prudent to seek a written opinion from a colleague to ensure that other forms of treatment may not be more appropriate. This may be the patient’s own GP or consultant who has been involved. In some jurisdictions parental permission may be required at this age. Health authorities or family services may also have to be involved in under-age cases, with details varying between jurisdictions.
As with other major treatment decisions, the patient should fully informed about its nature. This essential information should be given verbally, allowing for questions, as well as in writing. Various documents are available on the internet for patient education. Some documentation of consent should also be obtained in the patient records. Patients need to know that both methadone and buprenorphine have benefits and also certain side effects such as headache, constipation and sweating. The issue of cardiac conduction defects has never been shown to be a problem in patients being treated under dependency guidelines. However, for those taking higher doses (>150mg daily) or with other risk factors a cardiograph is a prudent step [ref 11].
Although many patients do attain opiate abstinence, methadone and buprenorphine treatments are not ‘cures’ for addiction. Patients should be aware that this is a treatment which requires regular attendance for medication, medical reviews, counselling and urine testing. They should also be informed that this treatment often lasts for months and sometimes for years. The myth of methadone being “for life” has been disproved by longitudinal studies with acronyms NTORS, ATOS, etc [ref 12]. Gossop points out that because clinics see successful patients less often than others, staff may develop the incorrect impression that few ever successfully withdraw from treatment.
Patients often arrive in distress and dismay, wanting to get into treatment urgently. It is still essential to ascertain who needs opioids and who may be more appropriate for detoxification services. Just because a patient says that they are in withdrawals does not mean that a doctor must write a prescription for opioids, although this should always be seriously considered as an option. Prescribing always has more predictable outcomes than detoxification. The doctor takes responsibility for the former and the patient the latter. Vincent Dole, the co-inventor of methadone treatment, said that “detoxification is an experiment in the life of the patient”
Who is best to provide such treatments? How is it done?
The delivery of methadone can occur in either the specialised clinic setting or in existing community facilities. There are advantages and disadvantages to both types, but ideally, new and unstable addiction cases would be treated in a specialised clinic. This allows close supervision for a period, after which stable and longer term patients could be referred back to GPs and pharmacists for community treatment. In practice there are usually more patients than services available so any treatment opportunity will have immediate applicants, most of whom are assessed as appropriate for maintenance treatment.
As with other acute presentations, one cannot do everything in the first consultation. However the basics need to be organized and a decision taken promptly as to whether or not the patient is to be prescribed opioids in a treatment ‘program’. At that point, one can afford to put off certain other matters until the patient feels better and has more confidence and familiarity with the staff and treatment setting. Another essential detail at this point is whether the patient has adequate housing considering they may be dispensed bottles of strong medicine. Also one needs to find out if there are children in the house and stress the importance of safe drug storage out of their reach.
The first dose.
The patient should usually be given a starting dose of 30mg with small increases in subsequent days up to the usual effective dose of 60 – 120mg. If given too quickly, drug accumulation can cause fatal toxicity so vigilance is needed in the first two weeks when this can occur. An additional 5 to 10mg every 2 to 3 days is usually a safe increase. On the other hand, if doses are kept too low, some patients will drop out while others may continue to use street drugs and/or alcohol. In some clinical settings it may be possible to give supplementary doses later the same day but only if the prescribing doctor has examined the patient 2 to 4 hours after the first dose. Where supplements are given, the second day’s dose should normally be the sum of the first day’s doses as long as there is no sign of toxicity.
Inductions onto buprenorphine are not as critical since early overdose is not a problem owing to the “ceiling effect” for respiratory depression. Most start with 4 to 8mg as a supervised sublingual dose, increasing only after 3 to 4 days when steady-state levels are achieved in this very long acting drug. Supplements may also be given, but these should be considered ‘loading doses’ and may only be needed in the first few days. The usual effective dose is 6 to 16mg daily with only a small proportion requiring more or less than this level. 32mg is the maximum daily dose.
Patients often know from previous experience how much they need and which drug suits them best. About a third of heroin addicts treated with buprenorphine will continue to feel drug cravings even when doses have been raised to the maximum of 32mg daily [ref 13]. Such patients usually do well on methadone using standard doses. For this and other reasons, methadone is probably still the best first line drug. A smaller proportion of methadone patients report unacceptable side effects such as sedation, sexual dysfunction, constipation or sweating and a transfer to buprenorphine can be very rewarding. However this can only be done ideally when the methadone dose has been reduced below 40mg daily due to the potential for a precipitated withdrawal episode as the partial opioid agonist buprenorphine replaces the full agonist methadone. This can be very unpleasant although it is usually short lived, in most cases less than one hour.
The first month of treatment is crucial to long term success. Hence it is essential to engage with the patient and establish a confident and professional relationship. This will involve all health care workers from reception staff to nursing, medical and pharmacists.
As with other conditions, management involves educating our patients, prescribing medications judiciously and supervising and monitoring progress. As with diabetes, depression or blood pressure, there is wide variation in views about how frequently patients may need to see a doctor, counsellor, pathology service or pharmacist. But the general principle is that new and unstable patients need more frequent and intensive involvement than long-term stable patients. Where there are psychologists, counsellors and other staff medical visits may be less frequent after the first month of treatment. There should be a formal interview each week until the patient shows signs of stability, then 2 to 4 weekly consultations should suffice for a year. Even very long term patients should probably see their prescriber every two months at a minimum.
Urine testing.
All patients who have come to the attention of dependency services should probably have urine testing at some frequency. This is essential at the initial assessment and twice yearly urine toxicology is probably a minimum for any person prescribed take-home doses of opioids, probably including pain management cases. Tests should be ‘supervised’ to some degree. The most useful tests for research or legal purposes will be directly witnessed and done at random. This is not always practical, nor is it necessary in most cases in clinical practice, unless the patient needs to prove their status for legal, family, sporting or sensitive employment matters. It is usually sufficient to ask for a urine test on a particular consultation day and have the staff test the temperature of the specimen. This may be done manually or using adherent temperature sensitive strips.
The interpretation of urine testing involves distinguishing non-specific ‘opiate’ positive tests from ‘morphine’ which is the breakdown product of heroin. One must take into account the half-lives of the cannabinoids, benzodiazepines, cocaine, amphetamine, etcetera. There should be no punitive outcomes from urine tests and these should only be used as a clinical indicator.
Dose supervision.
For new and unstable patients, as with other areas of medical practice, outcomes are directly related to compliance. The treatment of malaria, TB and HIV have each been shown to improve with directly observed treatment [refs 14,15]. Likewise with opioid therapies, witnessed doses improve outcomes and reduce the scope for diversion. In practice, most patients can be successfully treated by attending one to three times weekly depending on time in treatment, stability and dose level. The uniquely British practice of attendance at the pharmacy every one of two days to take bottles of medicine home is not based on any research and should be abandoned.
Cardinal rules for methadone:
The effective dose is generally 60-120mg daily with a small proportion needing more or less that this range due to unusual metabolism or tolerance. No more than 30mg should be given as a starting dose with increases of 5-10mg every 2-3 days, more rapidly only where close medical supervision is possible. Methadone should be avoided with fluvoxamine (inhibits metabolism), phenytoin or carbamazepine (induce metabolism) or pentazocine (may precipitate withdrawal, like buprenorphine). Special precautions are also necessary with various anti-HIV and TB drugs which may increase or decrease blood levels of methadone. Even grapefruit juice, with its effect on the cytochrome P450 enzymes can reduce methadone metabolism and raise levels. The principle is to carefully monitor any patient who is prescribed other drugs and be prepared to raise or lower the dose as appropriate – an examination 3-4 hours post-dose for signs of intoxication, and 24 hours afterwards for signs of withdrawal is generally more useful than measuring methadone blood levels [ref 16]. Patients should be warned not to drive, operate machinery or look after children until they are stable.
So what is needed for the future?
Treating addictions can be enormously rewarding and one does not have to wait for years to see the fruits of interventions. Many of these patients are ‘survivors’ who have enormous energy and resources which they often use to turn their lives around while in treatment. A ‘lapse’ back to drug use does not imply failure, but may mean that more attention needs to be paid to treatment. In cases of ‘relapse’, a second attempt at treatment is more likely to be successful than the first, especially if depression and anxiety are correctly dealt with.
All psychiatrists should be comfortable with treating dependency problems. There are some parallels between the management of nicotine, alcohol, opiate and stimulant addictions. Each has a behavioural and a chemical component. We should be aware of the differences and the similarities, each requiring appropriate interventions when required. Addictions are still inadequately covered in most undergraduate and family medicine training. Indeed, there was a time when some considered substance dependency not to be an area for doctors, nurses and pharmacists at all!
It is essential that consultant psychiatrists know how to set up and run a dependency unit within a community hospital setting. These will have the ability to take referrals with a view to assessments and a range of treatments, both medicated and non-medicated, based on rational, practical and cost-effective principles. As with general psychiatry, the great majority of such cases can be handled as out-patients but a small sub-set will need hospital admission. As with alcoholism, needs may vary from just brief respite care to acute care and intensive treatment. All the same principles of good medical practice should apply just as in every other medical specialty. While in treatment special attention needs to be paid to other areas of risk such as hepatitis C and other communicable diseases [ref 17].
Opioid maintenance treatment should be considered for all those who are addicted to either street heroin or pharmaceutical opioids and who are unable or unwilling to cease using such drugs. The same could be said for nicotine or, indeed, many medical situations where prescribing is only appropriate when non-drug approaches have failed or are inappropriate (eg. diabetes, hypertension, hyperlipidaemia).
For reasons which would be unacceptable in other fields, deficiencies in dependency treatments in the UK have undoubtedly contributed to the epidemics of HIV, hepatitis C, overdose and other consequences of addiction. It may take many years to turn these deficiencies around. Conceding them would be a great starting point. Methadone treatment has long been treated with great suspicion by the addiction ‘establishment’ in the UK. Indeed, Professor John Strang of the Maudsley Hospital has revealed his own misgivings about methadone by claiming that, despite its known benefits, it may have a ‘bitter final pathological twist’ (ref 18). Such personal reservations stand in stark contrast to 40 years of positive research findings, much published in the high rating journal, Addiction, of which he is an assistant editor.
References:
1. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. JAMA 1965 193:646-50
2. Thorley A. Longitudinal Studies of Drug Dependence. In: Drug Problems in Britain: A review of ten years. Eds: Edwards G, Busch C. 1981, Academic Press. p162
3. Greenwood J. Six years' experience of sharing the care of Edinburgh's drug users. Psychiatric Bulletin 1996 20:8-11
4. Stevenson RJ. Drug misusers are likely to abuse the system. BMJ 2007 335:317
5. McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The Effects of Psychosocial Services in Substance Abuse Treatment. JAMA 1993 269:1953-1959.
6. Drug Misuse and Dependence - Guidelines on Clinical Management. 1999 HMSO Department of Health. Working Group Chair: Strang J.
7. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. Brit J General Practice 2005 55;515:444-451
8. Caplehorn JRM, Dalton MSYN, Cluff MC, Petrenas A. Retention in methadone maintenance and heroin addicts' risk of death. Addiction 1994 89:203-7
9. Grönbladh L, Öhlund LS, Gunne LM. Mortality in heroin addiction: impact of methadone treatment. Acta Psychiatr Scand 1990 82:223-227
9b Gossop M, Marsden J, Stewart D, Treacy S. Outcomes after methadone maintenance and methadone reduction treatments: two-year follow-up results from the National Treatment Outcome Research Study. Drug and Alcohol Dep 2001 62;3:255-264
10. Self management and Recovery Training. http://www.smartrecovery.co.uk/ (accessed on 13/2/08).
11. Byrne A, Stimmel B. Methadone and QTc prolongation. Lancet 2007 369:366
12. Gossop M. The clinical fallacy and treatment outcomes. Addiction 2007 103:89
13. Kakko J, Grönbladh L, Svanborg KD, von Wachenfeldt J, Rück 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
14. Babudieri S, Aceti A, D'Offizi GP, Carbonara S, Starnini G. Directly Observed Therapy to Treat HIV Infection in Prisoners. JAMA 2000 284;2:179-180
15. Garner P, Volmink J. Directly observed treatment for tuberculosis. BMJ 2003 327:823-824
16. 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
17. 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
18. Strang J. Looking beyond death: paying attention to other important consequences of heroin overdose. Addiction 2002 97:927-928
Declaration of interest:
Dr Byrne’s addiction clinic charges a fee for dispensing methadone and buprenorphine.
8 September 2009
Torsade rarity: Annals responses argue ECG ineffective and unnecessary before MMT.
Krantz et al, Annals of Internal Medicine March 17: letters in reply, Aug 4 2009.
http://www.annals.org/cgi/content/full/151/3/216
http://www.annals.org/cgi/reprint/151/3/216
Dear Readers,
Each of four responses to this item was strongly critical of the position or Krantz et al. regarding cardiac safety in methadone patients. Apart from my own small contribution, there were considered responses from physicians and alumni of Johns Hopkins, Harvard and Rockefeller University as well as the medical director of a network of private addiction clinics treating 5000 methadone patients in California. There was no letter in support of Krantz et al and their “guidelines”.
Despite my written requests to Drs Krantz, Stimmel, Haigney and Martin, there is still no indication from these authors on the proposed means whereby regular ECG tracings would or could prevent torsade tachycardia from occurring in MMT patients. It would seem incumbent on Dr Krantz and colleagues to explain just how they anticipate the published recommendations might reduce cardiac side effects, and further, what might be the downside of the recommendation in terms of barriers to methadone treatment for those who want and need it both in developed and developing countries.
Krantz has written that cardiac safety in methadone treatment is a ‘national priority’ and that torsade is ‘potentially fatal’. Yet in 40 years there has still not been one confirmed death due to this complication in a methadone patient I can find in the literature. Out of ~100 case reports the great majority had complex medical scenarios including HIV, existing heart disease, metabolic disturbance and/or taking exceedingly high doses (mean 400mg daily in Krantz’s original report). These would only represent a small minority of those being assessed in addiction clinics around the world.
It is difficult to accept these guidelines in their present form when the main authors simply deflect criticism from senior colleagues rather than responding to it - see their response to the four letters.
Two original panel members declined to be associated with the publication and its recommendations. Their names were on the original internet version published around 1 Dec 2008 and now withdrawn. To my knowledge their dissenting views have not been published although the Annals editors took the rather unusual step of writing their own rapid response pointing out some of the facts following my initial communications: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1 (‘Putting the cart before the horse’). They also published a balanced and well considered editorial in the same hard-copy edition by Gourevitch.
I am still persuaded by the advice given by Dr Mori Krantz consistently from 2002 up until his Annals article this year that ECG is unnecessary before starting methadone treatment unless there is a specific indication (*see his quotes below). This is parallel with the views of other respected authors such as Krook, Athanasos, Gourevitch, Kreek, Bart and others.
We need a high level of awareness for numerous diseases and complications in older addiction patients. Cardiac conduction disturbance is just one of many such areas that we need to deal with. Although cardiac problems are dwarfed in scope by many other problems such as blood borne infections and hormonal imbalance, they should not be overlooked in known high risk groups.
In our own practice we generally order an electrocardiogram when the methadone dose exceeds 150mg daily and/or when there are other risk factors such as HIV, older age or other drug prescription known to affect methadone metabolism or cardiac conduction.
Comments by Andrew Byrne .. http://www.redfernclinic.com/c/
REFERENCES:
Original article: http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
Krantz on cardiac health in MMT patients (2001): http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388
Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
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
Gourevitch MN. First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;417-8
*Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368;9535:556-557 (quotes herewith from page 557)
“… we do not believe that routine ECG screening is warranted for heroin addicts entering treatment.”
“… we believe that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received.”
Possibly the last word: 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
http://www.annals.org/cgi/content/full/151/3/216
http://www.annals.org/cgi/reprint/151/3/216
Dear Readers,
Each of four responses to this item was strongly critical of the position or Krantz et al. regarding cardiac safety in methadone patients. Apart from my own small contribution, there were considered responses from physicians and alumni of Johns Hopkins, Harvard and Rockefeller University as well as the medical director of a network of private addiction clinics treating 5000 methadone patients in California. There was no letter in support of Krantz et al and their “guidelines”.
Despite my written requests to Drs Krantz, Stimmel, Haigney and Martin, there is still no indication from these authors on the proposed means whereby regular ECG tracings would or could prevent torsade tachycardia from occurring in MMT patients. It would seem incumbent on Dr Krantz and colleagues to explain just how they anticipate the published recommendations might reduce cardiac side effects, and further, what might be the downside of the recommendation in terms of barriers to methadone treatment for those who want and need it both in developed and developing countries.
Krantz has written that cardiac safety in methadone treatment is a ‘national priority’ and that torsade is ‘potentially fatal’. Yet in 40 years there has still not been one confirmed death due to this complication in a methadone patient I can find in the literature. Out of ~100 case reports the great majority had complex medical scenarios including HIV, existing heart disease, metabolic disturbance and/or taking exceedingly high doses (mean 400mg daily in Krantz’s original report). These would only represent a small minority of those being assessed in addiction clinics around the world.
It is difficult to accept these guidelines in their present form when the main authors simply deflect criticism from senior colleagues rather than responding to it - see their response to the four letters.
Two original panel members declined to be associated with the publication and its recommendations. Their names were on the original internet version published around 1 Dec 2008 and now withdrawn. To my knowledge their dissenting views have not been published although the Annals editors took the rather unusual step of writing their own rapid response pointing out some of the facts following my initial communications: http://www.annals.org/cgi/eletters/0000605-200903170-00103v1 (‘Putting the cart before the horse’). They also published a balanced and well considered editorial in the same hard-copy edition by Gourevitch.
I am still persuaded by the advice given by Dr Mori Krantz consistently from 2002 up until his Annals article this year that ECG is unnecessary before starting methadone treatment unless there is a specific indication (*see his quotes below). This is parallel with the views of other respected authors such as Krook, Athanasos, Gourevitch, Kreek, Bart and others.
We need a high level of awareness for numerous diseases and complications in older addiction patients. Cardiac conduction disturbance is just one of many such areas that we need to deal with. Although cardiac problems are dwarfed in scope by many other problems such as blood borne infections and hormonal imbalance, they should not be overlooked in known high risk groups.
In our own practice we generally order an electrocardiogram when the methadone dose exceeds 150mg daily and/or when there are other risk factors such as HIV, older age or other drug prescription known to affect methadone metabolism or cardiac conduction.
Comments by Andrew Byrne .. http://www.redfernclinic.com/c/
REFERENCES:
Original article: http://www.annals.org/cgi/content/full/0000605-200903170-00103v1
Krantz on cardiac health in MMT patients (2001): http://www.atforum.com/SiteRoot/pages/current_pastissues/fall2001.shtml#anchor1222388
Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
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
Gourevitch MN. First Do No Harm ... Reduction? Annals of Internal Medicine 2009 150;417-8
*Krantz MJ, Mehler PS. QTc prolongation: methadone's efficacy-safety paradox. Lancet 2006 368;9535:556-557 (quotes herewith from page 557)
“… we do not believe that routine ECG screening is warranted for heroin addicts entering treatment.”
“… we believe that the decision for ECG screening should not only be informed by the patient’s arrhythmia risk factors but also by the dose of methadone received.”
Possibly the last word: 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
30 June 2009
Cardiac complications in long-term methadone patients seem to be due to diverse factors.
Methadone induced long QTc and "torsade de pointe". Bittar P, Piguet V, Kondo-Oestreicher J et al. Swiss Medical Forum 2002 S4;P244:36S
Dear Colleagues,
This instructive case history which pre-dates Krantz’s report by several months, describes a long term methadone patient aged 39 developing ‘torsade de pointes’ a few days after starting triple therapy for HIV in the context of opioid withdrawal symptoms/signs and low blood levels. The patient also had chronic hepatitis C and epilepsy. As well as valproic acid for the latter, benzodiazepines, cannabis and alcohol were also involved in this seminal case.
The patient presented to the emergency room in opioid withdrawal. There was no electrolyte disturbance but methadone level was found to be ‘sub-therapeutic’ despite daily doses of 115mg administered by suppository (this is routinely used by some doctors in Switzerland). The QTc interval was available from a month before the episode at 480ms (normal less than 450mg).That cardiograph may have been ordered as part of a ‘work-up’ prior to starting anti-retroviral therapy but this is not detailed in the text.
While in hospital, 15 minutes following the daily rectal methadone dose the patient developed bradycardia, bigeminy and then torsade tachycardia. He was successfully resuscitated despite major seizures occurring simultaneously. The methadone was replaced by morphine 200mg twice daily which was associated with QTc interval reduction from 480 to 430ms.
Subsequent challenge a few days later with just 40mg methadone saw the QTc interval increase to 520ms and so the trial was abandoned due to the perceived risk. A cardiograph two weeks later showed the QTc interval to be still slightly elevated at 460ms despite the methadone having been long ceased. These observations are consistent with other evidence that methadone causes some modest prolongation of the QT interval and that this effect alone is generally of little clinical significance.
This patient took methadone, valproic acid, alcohol, cocaine and cannabis for at least 7 years without reported cardiac problems and so the onset of torsade during a period when the methadone level was low is hard to ascribe as a direct and dose-related effect. Rather, a combination of factors including possibly some myocardial ‘priming’ may be occurring.
This appears to be the very first of over 100 case reports in the literature of torsade de pointes in patients taking methadone maintenance for addiction. In nearly every case where details are available there were other drugs, extremely high dose, overdose, HIV and/or electrolyte disturbance reported. Pearson has called this a ‘threshold’ effect. Since methadone levels are sometimes in the low range it is possible that the drug is sometimes a ‘bystander’ while other drugs and/or the HIV virus itself might be responsible for the electrical instability in the heart.
Like others, these authors give some details of the management given to the patient. Even 7 years later, there still appears to be little agreement about an approach to treatment as cardiologists, intensivists and emergency physicians describe quite diverse approaches. These have included (1) efforts to maintain heart rate, (2) restoring electrolyte balance, (3) removal of triggering factors and (4) supportive measures. Magnesium and potassium infusions, administration of isoprenaline, atenalol, quinidine, lignocaine, amiodarone (!), glucoheptonate; implantable cardioverter-defibrillator (ICD); reducing methadone; continuing methadone; changing to morphine or buprenorphine. A review of such clinical manoeuvres by a cardiologist would be highly desirable in my view.
Instead of this logical step, Krantz and his panel have advised ‘discussions of risk’ (which are still largely unknown), pre-treatment ECG and continued QT interval monitoring. This is in the context of a lack of evidence for the effectiveness of such a strategy to prevent arrhythmias. Krantz’s group, in their extensive literature review of almost 100 papers left out numerous seemingly relevant articles (eg. Justo, Athanasos, Krook and Cruciani). It is hard to understand how the CSAT panel of experts could have completely overlooked these crucial papers, each of which is available on a simple internet search.
Further, despite the clear association with HIV infection (40% according to Justo), HIV is not even mentioned in the entire Annals paper from March 2009. The drugs gabapentin and ciprofloxacin come up in numerous reports, including 5 of Krantz’s original series of 9 pain management cases. Likewise, the issue of targeting strategies to those taking such medication is not emphasised by the CSAT panel report.
This early report from Switzerland contains some vital but conflicting evidence concerning causation. Like others, these authors find evidence of multifactorial causes for their patient’s torsade tachycardia. Yet there seems to be QT prolongation in relation to methadone dose levels, despite torsade occurring only very rarely in such cases. The cautious trial to reintroduce methadone caused QT prolongation but no arrhythmia. At the same time, it is questionable that a purported side effect of methadone would occur when the blood level was low and the patient was in a drug-induced withdrawal state.
Comments by Andrew Byrne ..
Clinic web page: http://www.redfernclinic.com/c/
References:
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
Krook AL, Waal H, Hansteen V. Routine ECG in methadone-assisted rehabilitation is wrong prioritization. Tidsskr Nor Laegeforen 2004 124;22:2940-1
Athanasos P, Farquharson AL, Compton P, Psaltis P, Hay J. Electrocardiogram characteristics of methadone and buprenorphine maintained subjects. J Addict Dis. 2008 27(3):31-5
Cruciani R. Methadone: To ECG or Not to ECG…That Is Still the Question. Journal of Pain and Symptom Management 2008 36;5:545-552
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