“Treatment for Pregnant Opioid Abuse Dependent Women”
Karol Kaltenbach, PhD
Clinical Associate Professor, Thomas Jefferson University, Jefferson Medical College
“Live at St Lukes”. Psychiatry Grand Rounds Wednesday 23rd March 2011.
This presentation was a well constructed description of the MOTHER study in a context somewhat removed from the science in my view.
Dr Kaltenbach began by saying that "Families I speak to are all real worried about babies withdrawing from drugs when they are born to mothers on methadone". She said that this was the main purpose of their study: to examine paediatric outcomes from pregnancies randomised to methadone or buprenorphine. We were reminded how little formal research has been done on opiate addicted mothers and their offspring even though tens of thousands of cases have been treated in the case of methadone which is considered the ‘gold standard’. While technically neither drug is approved in pregnancy, methadone treatment is considered a priority option for opioid dependent pregnant women in most health systems (and waiting lists are often dispensed with). Further, and reassuringly, to date several hundred babies have been reported born to mothers on buprenorphine. So the best ‘research’ has actually been field experience with this matter as well as scores of observational reports from Finnegan, Kandell and others. There have been no consistent problems reported from either group apart from the occurrence of neonatal abstinence syndrome (NAS). It is my belief that such concerns over NAS can be addressed by reassurance that existing treatments are satisfactory but may delay baby’s discharge by a few days in some cases.
To her credit Dr Kaltenbach stressed at the outset that from their findings and others’, NAS is no more or less likely with either drug, about half the babies exhibiting symptoms in both groups. We were then given an overview of the trial, initial 1074 screened candidates from seven sites (US, Canada, Austria) , 175 randomised to methadone (89) or buprenorphine (86) on double blind, double dummy bases and with 58 buprenorphine and 73 methadone subjects completing the study. We were briefly shown data supporting no substantive differences between the groups in the usual relevant demographic details including drug use (those dependent on sedatives or alcohol had been excluded at initial assessment). Then we saw numerous tables of primary outcomes and secondary outcomes of the study (all fetal results, including mostly non-significant differences - eg. NAS score, birth weight, head circumference, gestational age, etc). It was emphasised by the speaker that three fetal characteristics were significantly better in the buprenorphine group. These were (1) total amount of morphine used (2) infant’s hospital stay and (3) duration of NAS (I noted that these are all derivatives of the same thing, viz: the severity of NAS as perceived by the treating doctors). My feeling is that it is an overstatement to say that these are three (separate) beneficial findings.
To my mind this trial, for the first time, proved that methadone is the drug of choice for opioid dependency in pregnancy … it also showed that the 58 mothers who finally had a baby on buprenorphine (almost 1000 original applicants didn't) had babies with slightly less protracted and/or severe withdrawal syndromes. And this is no surprise since buprenorphine is the weaker agonist drug and thus mothers with more severe dependencies may be more likely to have dropped out. While the authors provided some comparative evidence against this, on the other hand it would appear to be supported by their finding that ten times as many of the buprenorphine drop-outs stated that they were 'dissatisfied with the medication' (20 versus 2 in the methadone drop-outs).
Dr Kaltenbach did emphasise the health care budget and the issue of hospital stays for treatment of NAS. More important than concerns over NAS in my experience is that most expectant parents want to know: 'will our baby grow up healthy?' NAS can be managed relatively simply and its occurrence is not known to be associated with any negative long term outcomes (Finnegan, personal communication). Most important are the proven negative outcomes known for pregnancies of opioid dependent women who are denied adequate treatment. The costs of such complications to the health system, insurance companies, managed care organisations and society generally are substantial and would be vastly more than even the most comprehensive opioid dependency treatment program.
Despite the modest benefits to the offspring and disastrous consequences to the retention rates, we were told that the researchers believed that their data supported a conclusion that buprenorphine is now a ‘first line option’ in pregnancy. Their institution’s press office went further, stating that that buprenorphine is ‘superior to methadone’ in pregnancy, something which I believe is patently untrue and highly misleading.
If indeed this trial were intended to fairly determine outcomes of the respective drugs then the analysis should have included the patients who ‘failed to comply with the protocols’ and were discharged from treatment. In my clinical experience involuntary 'discharges' are exceedingly rare and in most cases would be involuntary ‘transfers’ so treatment would not be curtailed under any circumstances against the wishes of the patient.
My impression from this presentation was that one of the main goals of this study was to support buprenorphine treatment in the community in America where methadone is often not available. Indeed the very title MOTHER would seem to indicate that fetal outcomes were secondary rather than primary. This is intriguing since buprenorphine is already being used widely in pregnancy with excellent results in those women who can tolerate it. In fact the main conclusion from this study is that both drugs are needed for such women since neither has sufficiently high retention rates. As Dr Kaltenbach implied early in her talk, such research during pregnancy has serious ethical limitations (and my feeling is that without a safety net this trial was in the same category).
A doctor in England tried to do a trial of this nature in non-pregnant patients and over a two year period in their busy treatment clinic she reported that she could not recruit one single patient to randomise (Pinto). It is of concern that in the ‘MOTHER’ study that subjects stood to earn up to $5800 in incentives for compliance and so this may explain why they were able to recruit the women, many of whom had been in stable methadone treatment at the time of joining the study (although this detail was not given in the paper or presentation but in a parallel publication by the group). Thus approximately half such stable patients had their prescribed medication altered during the trial. Such an incentive for a pregnant woman in stable treatment seems to me to be unfair and unbalanced. That such women consented to altered treatment is little justification or consolation for the excess number who dropped out of treatment in my view. Dr Kaltenbach implied that the incentives were used as a ‘normal’ part of high quality treatment, ensuring that there would be no criticism that the women were denied state-of-the-art medical attention. I have never heard of incentives of this degree being used or recommended as “contingency” management (the ‘rewards’ for ‘good behaviour’ are usually modest compared to these sums and sometimes the equivalent of bubble gum or lottery tickets). It appears inescapable, however, that this trial could not have gone ahead without some such strong incentives.
Another detail was that daily attendance, including weekends is an onerous task, especially during pregnancy and is hardly consistent with high quality treatment claimed by the researchers. Yet this is just one more deficiency in a very troublesome trial protocol.
At her talk Dr Kaltenbach seemed uncertain of the Canadian site situation (which ended up providing no subjects at all for the trial, rather like Dr Pinto in England). Initially she said that the patients had the opportunity to get pharmacy pick-ups and daily attendance was no longer acceptable to them. Later in response to my comments she said that there were problems getting the Subutex, Suboxone and placebos to the hospital in Canada.
Dr Kaltenbach stated that the researchers originally wanted to recruit 350 candidates but since the numbers were only about half that they changed their alpha significance level to 0.03 … something I confess I find bizarre and unconvincing. In my view a difference in outcomes is either significant or it isn’t using traditional p values for group comparisons. Even just looking at the raw figures on drop-outs I believe most concerned parties would be able to decide which group they would liked their family member or patient to be in.
Dr Kaltenbach described the excess drop-outs in the buprenorphine group as ‘pretty dramatic’. Yet there is a claim in the paper that this difference is not significantly different! We then had some speculation about the reasons behind the poor buprenorphine results, including inadequate induction doses or inadequate withdrawals before starting (and I wonder if it is ethical to induce withdrawals in pregnant women at all). The reader should note that this trial used pure buprenorphine (Subutex) which is the agent used in nearly all the quality research while the combination drug (Suboxone) has still not been subjected to much if any comparative research to my reading.
While Dr Kaltenbach said that there was no reason to do so, it seemed traditional nowadays to put up a disclosure notice. She said that there were no declarations of interest as she did no consultancies for drug companies.
Comments by Andrew Byrne ..
6 April 2011
Letter from New York ...
Dear Colleagues,
I have had the privilege of spending time in Manhattan meeting up with colleagues, mostly of like minds, on issues of mutual interest.
At the same time, Americans are often also interested in the drug situation in Australia including related viral diseases, public health and the various studies being reported. Of course I was most interested in innovations here in America, including the buprenorphine film/wafer which has been mooted by the manufacturer for quite some years to overcome some of the problems with their SL tablets. See http://www.attorneygeneral.gov/press.aspx?id=6035 It is about ten dollars cheaper than the tablets according to a pharmacist I interviewed here which may account for its popularity currently. It also has some disadvantages it would appear.
Other highlights: ‘MOTHER’ study presentation: http://methadone-research.blogspot.com/2011/04/mother-study-was-really-looking-babies.html This issue became a front page New York Times item last Sunday (links on request).
I visited the Drug Policy Alliance where there is a team of dedicated workers intent on improving harm reduction services in the United States and beyond. They are always keen to hear of progress in Australia, needle programs, injecting facilities, etcetera. Several of their workers have been to the Beirut Harm Reduction Conference earlier this month where they met up with numerous Australians.
Across the road in West 36th Street I met up with Lynn Paltrow at the National Advocates for Pregnant Women. We heard of tragic cases of ignorance in certain states where women on methadone were charged with ‘supplying a drug to a minor’ and being separated from their children as a result. While we all appreciate the great advances undertaken in the United States but it is also clear that there is a Neanderthal side to their approach to drugs and drug use (see warnings on every bottle of alcohol sold in the US but note there is no alcohol percentage noted, even on Fosters!). Their system just seems rigid and less flexible than in other places like Australia.
Grand Rounds at Bellevue Hospital had an interesting presentation on the use of peer mentors for alcohol and drug affected patients. Dr Kathlene Tracy had done two studies, one in the Veterans Administration and one at NYU, looking at attendances for appointments before and after engagement of a mentor (who had been carefully chosen and vetted as being at least 6 months ‘clean’. This ‘buddy’ engagement improved compliance substantially at very modest cost and deserves closer examination, especially for severely disrupted patients with no homes, telephones or other means of support. The staff members at Bellevue were most obliging and invited me to lunch where we had on-going discussions led by Dr Marc Galanter who is their senior D&A specialist.
I give Journal Club at Rockefeller University (Kreek Labs) on Tuesday before returning home for Easter and my father’s birthday on Lord Howe Island (he is 84!).
There is a meeting with the newly formed users’ group here which is lobbying for better access to treatment for hepatitis C. At present the only ‘mandated’ intervention is an antibody test at entry to methadone treatment. For buprenorphine even that can be overlooked.
Best wishes from Manhattan.
Andrew Byrne ..
I have had the privilege of spending time in Manhattan meeting up with colleagues, mostly of like minds, on issues of mutual interest.
At the same time, Americans are often also interested in the drug situation in Australia including related viral diseases, public health and the various studies being reported. Of course I was most interested in innovations here in America, including the buprenorphine film/wafer which has been mooted by the manufacturer for quite some years to overcome some of the problems with their SL tablets. See http://www.attorneygeneral.gov/press.aspx?id=6035 It is about ten dollars cheaper than the tablets according to a pharmacist I interviewed here which may account for its popularity currently. It also has some disadvantages it would appear.
Other highlights: ‘MOTHER’ study presentation: http://methadone-research.blogspot.com/2011/04/mother-study-was-really-looking-babies.html This issue became a front page New York Times item last Sunday (links on request).
I visited the Drug Policy Alliance where there is a team of dedicated workers intent on improving harm reduction services in the United States and beyond. They are always keen to hear of progress in Australia, needle programs, injecting facilities, etcetera. Several of their workers have been to the Beirut Harm Reduction Conference earlier this month where they met up with numerous Australians.
Across the road in West 36th Street I met up with Lynn Paltrow at the National Advocates for Pregnant Women. We heard of tragic cases of ignorance in certain states where women on methadone were charged with ‘supplying a drug to a minor’ and being separated from their children as a result. While we all appreciate the great advances undertaken in the United States but it is also clear that there is a Neanderthal side to their approach to drugs and drug use (see warnings on every bottle of alcohol sold in the US but note there is no alcohol percentage noted, even on Fosters!). Their system just seems rigid and less flexible than in other places like Australia.
Grand Rounds at Bellevue Hospital had an interesting presentation on the use of peer mentors for alcohol and drug affected patients. Dr Kathlene Tracy had done two studies, one in the Veterans Administration and one at NYU, looking at attendances for appointments before and after engagement of a mentor (who had been carefully chosen and vetted as being at least 6 months ‘clean’. This ‘buddy’ engagement improved compliance substantially at very modest cost and deserves closer examination, especially for severely disrupted patients with no homes, telephones or other means of support. The staff members at Bellevue were most obliging and invited me to lunch where we had on-going discussions led by Dr Marc Galanter who is their senior D&A specialist.
I give Journal Club at Rockefeller University (Kreek Labs) on Tuesday before returning home for Easter and my father’s birthday on Lord Howe Island (he is 84!).
There is a meeting with the newly formed users’ group here which is lobbying for better access to treatment for hepatitis C. At present the only ‘mandated’ intervention is an antibody test at entry to methadone treatment. For buprenorphine even that can be overlooked.
Best wishes from Manhattan.
Andrew Byrne ..
11 March 2011
A FEW RECENT JOURNAL ITEMS WHICH MAY INTEREST YOU.
Adding quetiapine (Seroquel) to naltrexone makes no difference to alcohol abstinence rates 61-72% at 4 months (Guardia et al in Barcelona).
No effect demonstrated in a good quality RCT of acamprosate for cocaine dependence (Kampman, O'Brien et al, Philadelphia).
Simojoki, Linzteris and Finland patients: “.. crushing of Subutex tablets does not significantly alter serum .. levels or the drug’s clinical effect ..”. They say crushing has no effect on dissolution time, contrary to our own experience (some chemists, cooks or clients may also disagree).
Cunningham et al compare buprenorphine induction at home with standard daily clinic initiation, finding some advantages in the home strategy … and few problems. This may be just what we need to reduce early treatment drop-outs for this otherwise excellent drug.
Extensive interviews with over 1000 pharmacotherapy patients show bimodal distribution for many aspects of dependency, indicating two categories of patients which are clinically distinct, justifying the DSM categories or levels of opioid dependence.
Strain et al compare cravings at induction of pure buprenorphine films (non-registered) versus buprenorphine/naloxone soluble-films (sometimes called wafers). It is disappointing that only the latter is being marketed because it is contraindicated in pregnancy yet women with young children are a target for measures against diversion and misuse which are claimed benefits of this formulation.
Pharmacist McNamara and colleagues select patients prescribed methadone for pain treatment and then report a (spurious) association with QT prolongation! Their paper has some interesting information but is no scientific treatise. One ‘high risk’ patient is on 5mg daily! One out of 7 patients died - not of torsade de pointes - but of ‘toxic shock’. Like most such papers, there are no cases of torsade. Nearly all (male) patients had QTc > 430ms BEFORE taking methadone(!). This is similar to Reddy’s paper from the Anderson Cancer Center.
The Iguana column in Addiction has rarely been a high point of scientific publication but this month makes no sense at all, at least to this antipodean reader. p685 [Full citations below]
Dear Colleagues,
These items are sent for your interest. I have not read them all fully but it is nice to see that our research colleagues are still working on basic efficacy trials using various combinations and comparisons. Some of these ‘stand up’ (like the superiority of methadone in pregnancy) while others reverse initial encouragement, such as the use of acamprosate for cocaine cravings. Both positive and negative findings are important to clinicians. The possibility of giving one or two initial doses of buprenorphine to candidates to take away and consume WHEN THEY ARE IN WITHDRAWAL may be a safe and beneficial innovation (Cunningham; Lee).
The first three items are high quality scientific comparisons (RCTs) while the last two items are here despite their poverty of content and rigour.
I hope they are of interest to readers.
Andrew Byrne ..
References:
Guardia J, Roncero C, Galan, J, Gonzalvo B, Burguete T, Casas M. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addictive Behaviors 2011 36;3:265-269
Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addictive Behaviors 2011 36;3:217-221
Simojoki K, Lillsunde P, Linzteris N, Alho H. Bioavailability of buprenorphine from crushed and whole buprenorphine (Subutex) tablets. Euro Addiction Res 2010 16;2:85-90
Cunningham CO, Giovanniello A, Li X, Kunins HV, Roose RJ, Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 2011
Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine 2009 24:226-232
Shand FL, Slade T, Degenhardt L, Baillie A, Nelson EC. Opioid dependence latent structure: two classes with differing severity? Addiction 2011 106:590-598 http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03217.x/abstract
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 26th Jan 2011 published on line ahead of print.
McNamara JK, Shinkazh N, Rim F, Zunga R, Cristian A. Methadone-Associated Prolongation of the QTc Interval at Doses Used for Chronic Pain. P&T February 2011 36;2:78-82 [references and conclusion on p107] http://www.nxtbook.com/nxtbooks/medimedia/pt_201102/#/28
News and Notes. Addiction 2011 p685
No effect demonstrated in a good quality RCT of acamprosate for cocaine dependence (Kampman, O'Brien et al, Philadelphia).
Simojoki, Linzteris and Finland patients: “.. crushing of Subutex tablets does not significantly alter serum .. levels or the drug’s clinical effect ..”. They say crushing has no effect on dissolution time, contrary to our own experience (some chemists, cooks or clients may also disagree).
Cunningham et al compare buprenorphine induction at home with standard daily clinic initiation, finding some advantages in the home strategy … and few problems. This may be just what we need to reduce early treatment drop-outs for this otherwise excellent drug.
Extensive interviews with over 1000 pharmacotherapy patients show bimodal distribution for many aspects of dependency, indicating two categories of patients which are clinically distinct, justifying the DSM categories or levels of opioid dependence.
Strain et al compare cravings at induction of pure buprenorphine films (non-registered) versus buprenorphine/naloxone soluble-films (sometimes called wafers). It is disappointing that only the latter is being marketed because it is contraindicated in pregnancy yet women with young children are a target for measures against diversion and misuse which are claimed benefits of this formulation.
Pharmacist McNamara and colleagues select patients prescribed methadone for pain treatment and then report a (spurious) association with QT prolongation! Their paper has some interesting information but is no scientific treatise. One ‘high risk’ patient is on 5mg daily! One out of 7 patients died - not of torsade de pointes - but of ‘toxic shock’. Like most such papers, there are no cases of torsade. Nearly all (male) patients had QTc > 430ms BEFORE taking methadone(!). This is similar to Reddy’s paper from the Anderson Cancer Center.
The Iguana column in Addiction has rarely been a high point of scientific publication but this month makes no sense at all, at least to this antipodean reader. p685 [Full citations below]
Dear Colleagues,
These items are sent for your interest. I have not read them all fully but it is nice to see that our research colleagues are still working on basic efficacy trials using various combinations and comparisons. Some of these ‘stand up’ (like the superiority of methadone in pregnancy) while others reverse initial encouragement, such as the use of acamprosate for cocaine cravings. Both positive and negative findings are important to clinicians. The possibility of giving one or two initial doses of buprenorphine to candidates to take away and consume WHEN THEY ARE IN WITHDRAWAL may be a safe and beneficial innovation (Cunningham; Lee).
The first three items are high quality scientific comparisons (RCTs) while the last two items are here despite their poverty of content and rigour.
I hope they are of interest to readers.
Andrew Byrne ..
References:
Guardia J, Roncero C, Galan, J, Gonzalvo B, Burguete T, Casas M. A double-blind, placebo-controlled, randomized pilot study comparing quetiapine with placebo, associated to naltrexone, in the treatment of alcohol-dependent patients. Addictive Behaviors 2011 36;3:265-269
Kampman KM, Dackis C, Pettinati HM, Lynch KG, Sparkman T, O'Brien CP. A double-blind, placebo-controlled pilot trial of acamprosate for the treatment of cocaine dependence. Addictive Behaviors 2011 36;3:217-221
Simojoki K, Lillsunde P, Linzteris N, Alho H. Bioavailability of buprenorphine from crushed and whole buprenorphine (Subutex) tablets. Euro Addiction Res 2010 16;2:85-90
Cunningham CO, Giovanniello A, Li X, Kunins HV, Roose RJ, Sohler NL. A comparison of buprenorphine induction strategies: Patient-centered home-based inductions versus standard-of-care office-based inductions. Journal of Substance Abuse Treatment 2011
Lee JD, Grossman E, DiRocco D, Gourevitch MN. Home buprenorphine/naloxone induction in primary care. Journal of General Internal Medicine 2009 24:226-232
Shand FL, Slade T, Degenhardt L, Baillie A, Nelson EC. Opioid dependence latent structure: two classes with differing severity? Addiction 2011 106:590-598 http://onlinelibrary.wiley.com/doi/10.1111/j.1360-0443.2010.03217.x/abstract
Strain EC, Harrison JA, Bigelow GE. Induction of Opioid-Dependent Individuals Onto Buprenorphine and Buprenorphine/Naloxone Soluble-Films. Clinical Pharmacology and Therapeutics 26th Jan 2011 published on line ahead of print.
McNamara JK, Shinkazh N, Rim F, Zunga R, Cristian A. Methadone-Associated Prolongation of the QTc Interval at Doses Used for Chronic Pain. P&T February 2011 36;2:78-82 [references and conclusion on p107] http://www.nxtbook.com/nxtbooks/medimedia/pt_201102/#/28
News and Notes. Addiction 2011 p685
22 February 2011
Possibly the last case report of torsade in a methadone patient. Now, how to treat it?
Torsade de Pointes due to Methadone Use in a Patient with HIV and Hepatitis C Coinfection. John J, Amley X, Bombino G, Gitelis C, Topi B, Hollander G, Ghosh J. Cardiol Res Pract. 2010; 2010: 524764
Dear Colleagues,
This case history is instructive although it is not novel. To call this torsade "due to methadone" in the title is highly misleading and contrary to the paper’s data.
The daily methadone dose was low at 40mg (and ‘recently increased’); the patient was aged 50 and was also prescribed three antiviral agents and two antibiotics for HIV. These factors made the patient easily identifiable as a high risk case for numerous medical complications including torsade de pointes tachycardia. Importantly, one of the HIV drugs used has been reported elsewhere to cause torsade (atazanavir, as reported by Dabiesingh; Ly and others). Hence older age, atazanavir and HIV are thus all known to be specific risk factors for developing QT problems. There is also some evidence that HCV may be an independent risk factor for QT prolongation (Norden). From the literature I have searched it seems that most HIV subjects with torsade de pointes are not taking methadone.
Unfortunately, details of this patient’s dependency management are scanty and it seems that there was limited if any addiction specialty input. Note that the patient survived and even 23 days after the methadone was ceased still had QT prolongation and was considered to be in need of a pacemaker (ICD). The reader is not informed, but methadone may have been substituted by another drug, such as morphine. Either way, it would seem to indicate that the methadone was NOT the cause of the electrical perturbations in this patient, despite the alarmist title.
The authors concede that a dose level of 40mg (increased two months before the episode following two years of no illicit drug use) is very unlikely to be a significant causative factor for QT prolongation. The methadone may even have delayed the onset of torsade, for example, by keeping the patient from other cardio-toxic drugs including alcohol, cocaine and amphetamine. It is paradoxical that this very patient was administered another QT prolonging drug, the anti-arrhythmic amiodarone during resuscitation. This drug is similar to methadone in that it can reportedly cause QT prolongation but rarely induces torsade.
These authors cite Adelaide author Athanasos but do so rather selectively. While he does indeed describe U-waves, of uncertain clinical significance, his study found no cardiologic consequences of low to medium doses of methadone, the latter findings appear to be ignored in the current paper. It is intriguing that these authors would repeat Krantz and colleagues’ controversial and unproven advice (Ann Int Med) about performing annual ECGs on methadone patients (see responses in Annals, 4 against, none in favour). This very case report is yet another example in which such serial ECGs were performed and yet torsade occurred regardless. It seems that in America performing a test is sometimes seen as a defence regardless of its utility or otherwise.
That this patient is alive at 50 after having such serious complications of IV drug use as HCV, HIV and hepatoma is indeed a credit to the methadone and medical care received at this institution bearing the name of one of the most innovative doctors of all time, Maimonides (see his treatises on haemorrhoids, digestion, chicken soup and cohabitation).
Reports of torsade in methadone patients are not usually published any more, probably because the details are similar to over 100 other such reports - it would be like describing a 'routine' case of appendicitis. Furthermore, there have apparently been no fatalities from confirmed torsade to date to my best knowledge, at least in the past 15 years (an American text states that it should have a mortality of zero). According to the Journal's web site these authors would have paid over US$500 to have this vignette made public.
If nothing more, the report should be a wake-up call to all who treat middle aged opioid dependent patients and remind us to take greatest care when anti-virals, anti-fungals, antibiotics, etc are being prescribed, especially by others who may not be familiar with the dependency side of their patient’s treatment. The size of the methadone dose appears to be of little relevance (Krantz’s original series had 6 of 9 subjects taking between 65mg and 125mg, mean 96mg daily; Pearson reports one case at 29mg daily).
Comments by Andrew Byrne ..
Link to article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021856/
Correction for Jones article summary: I stated in an early draft that there was no fetal loss but in fact there were two such events, both in the methadone group. This was promptly corrected on the web site and I apologise for the mistake. Dr Jones has also pointed out that the trend for greater attrition in the buprenorphine group did not reach statistical significance. To my mind the authors have still not justified their comment that buprenorphine is now a ‘first line option’. Just because they showed no difference in retention/attrition, this does not prove that the two treatments are equivalent therapeutically. I believe that both drugs are extremely useful in opioid dependency and that methadone remains the gold standard (O’Connor 2010 JAMA) although it does not suit everyone or every situation.
Dear Colleagues,
This case history is instructive although it is not novel. To call this torsade "due to methadone" in the title is highly misleading and contrary to the paper’s data.
The daily methadone dose was low at 40mg (and ‘recently increased’); the patient was aged 50 and was also prescribed three antiviral agents and two antibiotics for HIV. These factors made the patient easily identifiable as a high risk case for numerous medical complications including torsade de pointes tachycardia. Importantly, one of the HIV drugs used has been reported elsewhere to cause torsade (atazanavir, as reported by Dabiesingh; Ly and others). Hence older age, atazanavir and HIV are thus all known to be specific risk factors for developing QT problems. There is also some evidence that HCV may be an independent risk factor for QT prolongation (Norden). From the literature I have searched it seems that most HIV subjects with torsade de pointes are not taking methadone.
Unfortunately, details of this patient’s dependency management are scanty and it seems that there was limited if any addiction specialty input. Note that the patient survived and even 23 days after the methadone was ceased still had QT prolongation and was considered to be in need of a pacemaker (ICD). The reader is not informed, but methadone may have been substituted by another drug, such as morphine. Either way, it would seem to indicate that the methadone was NOT the cause of the electrical perturbations in this patient, despite the alarmist title.
The authors concede that a dose level of 40mg (increased two months before the episode following two years of no illicit drug use) is very unlikely to be a significant causative factor for QT prolongation. The methadone may even have delayed the onset of torsade, for example, by keeping the patient from other cardio-toxic drugs including alcohol, cocaine and amphetamine. It is paradoxical that this very patient was administered another QT prolonging drug, the anti-arrhythmic amiodarone during resuscitation. This drug is similar to methadone in that it can reportedly cause QT prolongation but rarely induces torsade.
These authors cite Adelaide author Athanasos but do so rather selectively. While he does indeed describe U-waves, of uncertain clinical significance, his study found no cardiologic consequences of low to medium doses of methadone, the latter findings appear to be ignored in the current paper. It is intriguing that these authors would repeat Krantz and colleagues’ controversial and unproven advice (Ann Int Med) about performing annual ECGs on methadone patients (see responses in Annals, 4 against, none in favour). This very case report is yet another example in which such serial ECGs were performed and yet torsade occurred regardless. It seems that in America performing a test is sometimes seen as a defence regardless of its utility or otherwise.
That this patient is alive at 50 after having such serious complications of IV drug use as HCV, HIV and hepatoma is indeed a credit to the methadone and medical care received at this institution bearing the name of one of the most innovative doctors of all time, Maimonides (see his treatises on haemorrhoids, digestion, chicken soup and cohabitation).
Reports of torsade in methadone patients are not usually published any more, probably because the details are similar to over 100 other such reports - it would be like describing a 'routine' case of appendicitis. Furthermore, there have apparently been no fatalities from confirmed torsade to date to my best knowledge, at least in the past 15 years (an American text states that it should have a mortality of zero). According to the Journal's web site these authors would have paid over US$500 to have this vignette made public.
If nothing more, the report should be a wake-up call to all who treat middle aged opioid dependent patients and remind us to take greatest care when anti-virals, anti-fungals, antibiotics, etc are being prescribed, especially by others who may not be familiar with the dependency side of their patient’s treatment. The size of the methadone dose appears to be of little relevance (Krantz’s original series had 6 of 9 subjects taking between 65mg and 125mg, mean 96mg daily; Pearson reports one case at 29mg daily).
Comments by Andrew Byrne ..
Link to article: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021856/
Correction for Jones article summary: I stated in an early draft that there was no fetal loss but in fact there were two such events, both in the methadone group. This was promptly corrected on the web site and I apologise for the mistake. Dr Jones has also pointed out that the trend for greater attrition in the buprenorphine group did not reach statistical significance. To my mind the authors have still not justified their comment that buprenorphine is now a ‘first line option’. Just because they showed no difference in retention/attrition, this does not prove that the two treatments are equivalent therapeutically. I believe that both drugs are extremely useful in opioid dependency and that methadone remains the gold standard (O’Connor 2010 JAMA) although it does not suit everyone or every situation.
15 February 2011
Like randomised trials, patient choosing methadone also have much better retention.
The SUMMIT Trial: A field comparison of buprenorphine versus methadone maintenance treatment. Pinto H, Maskrey V, Swift L, Rumball D, Wagle A, Holland R. Journal of Substance Abuse Treatment, 2010 39;4:340-352
Dear Reader,
This naturalistic description and follow up study from a drug service in England shows comparative retention rates in opiate maintenance patients with exhaustive comparisons between the two groups. The current study followed a previous abortive attempt at randomisation of the groups which failed to attract any subjects, so determined were they all on their preferred medication.
These authors enrolled 361 eligible applicants for opioid maintenance of whom 227 (63%) chose methadone with the rest opting for (pure) buprenorphine (37%).
Despite the methadone patients having ‘more severe substance abuse and psychiatric and physical problems’ their retention rate was substantially higher than the buprenorphine patients (70% vs. 43% at 6 months).
Only seven of 134 patients swapped from buprenorphine to methadone early in the trial (apparently none swapped the other way around). Of the remaining buprenorphine drop-outs 10 were planned detox episodes; 40 failed to attend; 13 were detained by police; 10 were involuntary discharges. Relating to buprenorphine retention the authors report that the only significant difference on multivariate analysis in the many features/opinions solicited from the subjects was a ‘belief as to whether buprenorphine blocked the effect of heroin’. While this belief is not soundly based, it might be a helpful street myth, keeping some patients away from dangerous drugs. However, it could also give some users a false sense of security in a high risk overdose situation.
The trial patients were prescribed a mean maximum daily dose for buprenorphine of 12mg (r 4-20mg); and for methadone of 73mg (r 10-170mg). There were two deaths in the methadone group, one in the induction period and another while on a stable dose of methadone caused by overdose of multiple depressants.
As in most such longitudinal studies the proportion of subjects successfully reducing their dose to zero was low - around 7% for buprenorphine and under 1% for those choosing methadone during a six month period. This is consistent with other research showing about 4% of opioid dependent people become abstinent each year (and this is regardless of the type of treatment - see Thorley’s seminal work from the UK).
Crucial to the results of this trial was the finding that 10% of the total said that they would not have attended if methadone were the only drug available. The derived figure of buprenorphine patients who stated that they would not have attended for methadone in the absence of an alternative was 28%. This is a novel finding to my knowledge but fits with clinical experience in other areas that greater choice yields greater patient acceptance, better enrolments, compliance (adherence) and retention. Apparently English health authorities are required to justify the expense of each medication and so this provides strong evidence in that regard which was one of the aims of the authors (see their previous paper).
Since these authors used pure buprenorphine SL tablets readers should be cautious about extrapolating these findings to buprenorphine-naloxone (Suboxone) … it may or may not be the case that buprenorphine-naloxone would have achieved similar results to pure buprenorphine on which most of the fundamental research has been performed to date (RCT, safety, etc). Another reason to favour pure buprenorphine is that it is available in 0.4mg tablets (in Australia). In our own practice we have at least a quarter of our patients taking increments requiring 0.4mg tablets.
While there must be end-points to any research trial, it would be instructive to know how many of the drop-outs had re-registered in treatment (if any). While the group was not able to examine this issue, other research would indicate largely negative results including a high mortality. Dr Bell investigated this from official enrolment statistics in New South Wales some years ago [Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug and Alcohol Dependence 2006 81; 1: 55-61]. Such research, as well as clinical experience with buprenorphine shows that there is indeed a ‘revolving door’ or ‘frequent flyer’ syndrome with this treatment, at least in comparison to methadone.
Because there was no randomisation to the intervention, this study does not give us scientific information about the different drugs. However, it does inform us for the first time I believe that the most seriously dependent patients are more likely to choose methadone and that they have a better retention rate in so doing. Less seriously dependent patients are more likely to choose buprenorphine and are more likely to drop out of treatment (and some successfully withdraw from treatment). So unsurprisingly, outcomes are a function of both the patient group and the treatment chosen. While this information is not a major benefit in individual clinical decision making, this study at the very least provides an excellent “barometer” by which we might measure our own practices regarding the proportion taking each drug and the dose ranges used.
Comments by Andrew Byrne ..
Dear Reader,
This naturalistic description and follow up study from a drug service in England shows comparative retention rates in opiate maintenance patients with exhaustive comparisons between the two groups. The current study followed a previous abortive attempt at randomisation of the groups which failed to attract any subjects, so determined were they all on their preferred medication.
These authors enrolled 361 eligible applicants for opioid maintenance of whom 227 (63%) chose methadone with the rest opting for (pure) buprenorphine (37%).
Despite the methadone patients having ‘more severe substance abuse and psychiatric and physical problems’ their retention rate was substantially higher than the buprenorphine patients (70% vs. 43% at 6 months).
Only seven of 134 patients swapped from buprenorphine to methadone early in the trial (apparently none swapped the other way around). Of the remaining buprenorphine drop-outs 10 were planned detox episodes; 40 failed to attend; 13 were detained by police; 10 were involuntary discharges. Relating to buprenorphine retention the authors report that the only significant difference on multivariate analysis in the many features/opinions solicited from the subjects was a ‘belief as to whether buprenorphine blocked the effect of heroin’. While this belief is not soundly based, it might be a helpful street myth, keeping some patients away from dangerous drugs. However, it could also give some users a false sense of security in a high risk overdose situation.
The trial patients were prescribed a mean maximum daily dose for buprenorphine of 12mg (r 4-20mg); and for methadone of 73mg (r 10-170mg). There were two deaths in the methadone group, one in the induction period and another while on a stable dose of methadone caused by overdose of multiple depressants.
As in most such longitudinal studies the proportion of subjects successfully reducing their dose to zero was low - around 7% for buprenorphine and under 1% for those choosing methadone during a six month period. This is consistent with other research showing about 4% of opioid dependent people become abstinent each year (and this is regardless of the type of treatment - see Thorley’s seminal work from the UK).
Crucial to the results of this trial was the finding that 10% of the total said that they would not have attended if methadone were the only drug available. The derived figure of buprenorphine patients who stated that they would not have attended for methadone in the absence of an alternative was 28%. This is a novel finding to my knowledge but fits with clinical experience in other areas that greater choice yields greater patient acceptance, better enrolments, compliance (adherence) and retention. Apparently English health authorities are required to justify the expense of each medication and so this provides strong evidence in that regard which was one of the aims of the authors (see their previous paper).
Since these authors used pure buprenorphine SL tablets readers should be cautious about extrapolating these findings to buprenorphine-naloxone (Suboxone) … it may or may not be the case that buprenorphine-naloxone would have achieved similar results to pure buprenorphine on which most of the fundamental research has been performed to date (RCT, safety, etc). Another reason to favour pure buprenorphine is that it is available in 0.4mg tablets (in Australia). In our own practice we have at least a quarter of our patients taking increments requiring 0.4mg tablets.
While there must be end-points to any research trial, it would be instructive to know how many of the drop-outs had re-registered in treatment (if any). While the group was not able to examine this issue, other research would indicate largely negative results including a high mortality. Dr Bell investigated this from official enrolment statistics in New South Wales some years ago [Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990–2002. Drug and Alcohol Dependence 2006 81; 1: 55-61]. Such research, as well as clinical experience with buprenorphine shows that there is indeed a ‘revolving door’ or ‘frequent flyer’ syndrome with this treatment, at least in comparison to methadone.
Because there was no randomisation to the intervention, this study does not give us scientific information about the different drugs. However, it does inform us for the first time I believe that the most seriously dependent patients are more likely to choose methadone and that they have a better retention rate in so doing. Less seriously dependent patients are more likely to choose buprenorphine and are more likely to drop out of treatment (and some successfully withdraw from treatment). So unsurprisingly, outcomes are a function of both the patient group and the treatment chosen. While this information is not a major benefit in individual clinical decision making, this study at the very least provides an excellent “barometer” by which we might measure our own practices regarding the proportion taking each drug and the dose ranges used.
Comments by Andrew Byrne ..
21 December 2010
Say no to "just say no"! Give in, with therapeutic strings.
Article printed in "OF SUBSTANCE".
"View from the coal face" … in Redfern, inner Sydney.
Commentary on Addiction editorial on benzodiazepine maintenance.
After many years of wrestling with the problem of benzodiazepine use in opioid dependency patients it was reassuring to read the prominent paper by Liebrenz and colleagues. Their hypothesis is an approach using what appear to be harm reduction principles, parallel to methadone maintenance. Our original practice policy was to ‘just say no’ but despite our entreaties, about one third of our patients continued to use benzodiazepines on urine testing. A number did succeed at abstinence, only to relapse with significant harms occurring due to disinhibited behaviour, often involving amnesia for the events.
Some patients were able to function almost normally while taking illicit benzodiazepines. Others became disorganised regarding their finances, housing and interpersonal relationships, some even coming to the attention of the police or emergency departments.
Although there appeared to be a number of patters of tranquillizer use, from binge and recreational use to quasi-therapeutic, we treated all such patients the same way initially, using diazepam 5mg tablets supervised at the clinic. Those currently abusing alcohol were excluded. Each patient needed to return at least once, about 3 hours after a witnessed dose for a brief examination to confirm their tolerance and exclude intoxication. All patients also had to agree to random urine testing and regular medical consultations to assess progress.
Our impression has been that when given access to diazepam under close supervision, stability returned to most such patients. A recent audit of our referral dependency practice showed that of 167 pharmacotherapy patients, (80% methadone, 20% buprenorphine) 30% were being prescribed benzodiazepines, mostly under supervision at the practice. The mean dose was 14mg daily (range 2mg - 25mg). One third were gainfully employed.
Thus we can confirm that some of the protocols alluded to in the forward thinking item in Addiction are feasible and are ripe for research. Enquiries showed that many of our colleagues had one or two pharmacotherapy patients taking long-term benzodiazepines and nearly all had organised supervised dosing at least once.
Benzodiazepine use has been the ‘elephant in the room’ in addiction treatment. While many centres still use an abstinence approach, many patients continue to use these drugs. Since benzodiazepines, along with alcohol, constitute a major source of drug-related harm it may be timely to reassess our approach. Severe restrictions on supply alone have historically never solved drug problems. Such restrictions also necessarily reduce access to those who need the drugs therapeutically. As with many other areas of public health, we believe that it is possible to translate the principles of ‘harm reduction’ to benzodiazepine use by utilizing the protocols of ‘universal precautions’ espoused by Dr Gourlay in Canada.
The use of benzodiazepine maintenance is probably at the same stage of ‘evidence’ as methadone treatment was in about 1980. It appears to be acceptable to the patient population; it appears to be safe in practice, yet definitive research is awaited to prove its effects … and to identify optimal dosing, supports and necessary supervision. Likewise oral morphine, injectable methadone and heroin assisted treatments are being trialled in several countries currently. Thus in our own patient group we found that supervised, low dose diazepam was worth offering to those who were unable or unwilling to give up benzodiazepines.
References:
Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874
Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med (2005) 6;2:107-112
Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. D&A Review 2010 29:3:250-255
Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 23;8:1584-1585
See article summary by Libby Topp http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf
"View from the coal face" … in Redfern, inner Sydney.
Commentary on Addiction editorial on benzodiazepine maintenance.
After many years of wrestling with the problem of benzodiazepine use in opioid dependency patients it was reassuring to read the prominent paper by Liebrenz and colleagues. Their hypothesis is an approach using what appear to be harm reduction principles, parallel to methadone maintenance. Our original practice policy was to ‘just say no’ but despite our entreaties, about one third of our patients continued to use benzodiazepines on urine testing. A number did succeed at abstinence, only to relapse with significant harms occurring due to disinhibited behaviour, often involving amnesia for the events.
Some patients were able to function almost normally while taking illicit benzodiazepines. Others became disorganised regarding their finances, housing and interpersonal relationships, some even coming to the attention of the police or emergency departments.
Although there appeared to be a number of patters of tranquillizer use, from binge and recreational use to quasi-therapeutic, we treated all such patients the same way initially, using diazepam 5mg tablets supervised at the clinic. Those currently abusing alcohol were excluded. Each patient needed to return at least once, about 3 hours after a witnessed dose for a brief examination to confirm their tolerance and exclude intoxication. All patients also had to agree to random urine testing and regular medical consultations to assess progress.
Our impression has been that when given access to diazepam under close supervision, stability returned to most such patients. A recent audit of our referral dependency practice showed that of 167 pharmacotherapy patients, (80% methadone, 20% buprenorphine) 30% were being prescribed benzodiazepines, mostly under supervision at the practice. The mean dose was 14mg daily (range 2mg - 25mg). One third were gainfully employed.
Thus we can confirm that some of the protocols alluded to in the forward thinking item in Addiction are feasible and are ripe for research. Enquiries showed that many of our colleagues had one or two pharmacotherapy patients taking long-term benzodiazepines and nearly all had organised supervised dosing at least once.
Benzodiazepine use has been the ‘elephant in the room’ in addiction treatment. While many centres still use an abstinence approach, many patients continue to use these drugs. Since benzodiazepines, along with alcohol, constitute a major source of drug-related harm it may be timely to reassess our approach. Severe restrictions on supply alone have historically never solved drug problems. Such restrictions also necessarily reduce access to those who need the drugs therapeutically. As with many other areas of public health, we believe that it is possible to translate the principles of ‘harm reduction’ to benzodiazepine use by utilizing the protocols of ‘universal precautions’ espoused by Dr Gourlay in Canada.
The use of benzodiazepine maintenance is probably at the same stage of ‘evidence’ as methadone treatment was in about 1980. It appears to be acceptable to the patient population; it appears to be safe in practice, yet definitive research is awaited to prove its effects … and to identify optimal dosing, supports and necessary supervision. Likewise oral morphine, injectable methadone and heroin assisted treatments are being trialled in several countries currently. Thus in our own patient group we found that supervised, low dose diazepam was worth offering to those who were unable or unwilling to give up benzodiazepines.
References:
Liebrenz M, Boesch L, Stohler R, Caflisch C. Agonist substitution-a treatment alternative for high-dose benzodiazepine-dependent patients? Addiction 2010 105;11:1870–1874
Gourlay DL, Heit HA, Almahrezi A. Universal precautions in pain medicine: a rational approach to the treatment of chronic pain. Pain Med (2005) 6;2:107-112
Darke S, Ross J, Mills K, Teesson M, Williamson A, Harvard A. Benzodiazepine use among heroin users: Baseline use, current use and clinical outcome. D&A Review 2010 29:3:250-255
Byrne A. Benzodiazepines: the end of a dream. Aust Fam Physician 1994 23;8:1584-1585
See article summary by Libby Topp http://www.ofsubstance.org.au/images/archive/pdf/ofsubstance_2010_3.pdf
17 December 2010
More drop-outs with buprenorphine in pregnancy.
Reduced retention makes buprenorphine a poor second to methadone in pregnancy.
Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM 2010; 363:2320-2331
Dear Colleagues,
These authors assessed 1074 pregnant women from clinics in Austria, Canada and the USA for this comparison of methadone and buprenorphine regarding neonatal abstinence syndrome (NAS). There were 250 who declined to participate and another 650 did not fit inclusion criteria (alcohol, benzo use, medical conditions, for example) leaving 175 in the randomised comparison groups, blinded by a morphine wash-out period in hospital and use of ‘double dummy’ placebo. Pure buprenorphine (Subutex) was used to avoid prenatal exposure to naloxone (Suboxone is contraindicated in pregnancy). Over $1000 was available to subjects contingent on clear urine toxicology during the trial.
There were two peri-natal deaths reported from those who remained in the study, one from each group. There were two miscarriages (both in the MMT group). “The percentage of neonates requiring NAS treatment did not differ significantly between groups (P = 0.26), nor did the groups differ significantly with respect to the peak NAS score (P = 0.04) or head circumference (P = 0.04).” However, two other primary outcomes were significantly better in the buprenorphine group: (1) quantities of morphine used for neonatal abstinence syndrome (NAS) and (2): ‘total hospital stay’. The prognostic significance of these outcomes is unknown to my best knowledge.
The numbers of enrolled subjects were not large enough to show anything but very major outcome effects as being statistically significant. Previous experience has consistently shown only modest differences between methadone and buprenorphine regarding neonatal outcomes. Hence this trial was under-powered on the numbers to find minor differences to statistical significance.
Aside from the unsurprising neonatal outcomes, there were some dramatic and remarkable maternal findings which are mentioned but not brought to the prominence they deserve in my view. These differences are so great that they may even invalidate the neonatal findings (for example if those with high tolerance or rapid metabolism were more likely to drop out).
To my mind the two most important findings of the study are as follows:
The methadone group (n=89) had 16 drop-outs (18%) while the buprenorphine group (n=86) had 28 drop-outs (33%) [p=0.02]. Even more dramatic, of the 16 methadone drop-outs, 2 were due to ‘dissatisfaction with the medication’ while the corresponding number for the buprenorphine candidates was 20, a massive difference. These findings are discussed in the text but should probably also be enshrined in the title of the article. There is no point in having favourable neonatal outcomes if a third of the mothers have left treatment before term.
Even with its failings, I believe that this study provides the most persuasive evidence to date showing the safety and effectiveness of methadone in pregnancy. Indeed, it clearly demonstrates that, in the absence of contraindications, methadone should be the first line drug for opiate dependence in pregnancy (as in the non-pregnant). Yet despite their finding that almost twice as many women dropped out in the buprenorphine group, these authors state, somewhat clumsily: “Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy.”
Rather than an option, “first line” status implies an obligation in my book. Since buprenorphine is the only alternative medication licensed for opioid dependence then it is obviously an ‘option’, if a somewhat less effective one. This RCT confirms that during pregnancy, consistent with the existing body of research evidence, (pure) buprenorphine should be the second line drug and only used when methadone is found to be clinically inappropriate. I believe that it is unethical to prescribe Suboxone (buprenorphine/naloxone).
Comments by Andrew Byrne ..
http://methadone-research.blogspot.com/
Jones HE, Kaltenbach K, Heil SH, Stine SM, Coyle MG, Arria AM, O'Grady KE, Selby P, Martin PR, Fischer G. Neonatal Abstinence Syndrome after Methadone or Buprenorphine Exposure. NEJM 2010; 363:2320-2331
Dear Colleagues,
These authors assessed 1074 pregnant women from clinics in Austria, Canada and the USA for this comparison of methadone and buprenorphine regarding neonatal abstinence syndrome (NAS). There were 250 who declined to participate and another 650 did not fit inclusion criteria (alcohol, benzo use, medical conditions, for example) leaving 175 in the randomised comparison groups, blinded by a morphine wash-out period in hospital and use of ‘double dummy’ placebo. Pure buprenorphine (Subutex) was used to avoid prenatal exposure to naloxone (Suboxone is contraindicated in pregnancy). Over $1000 was available to subjects contingent on clear urine toxicology during the trial.
There were two peri-natal deaths reported from those who remained in the study, one from each group. There were two miscarriages (both in the MMT group). “The percentage of neonates requiring NAS treatment did not differ significantly between groups (P = 0.26), nor did the groups differ significantly with respect to the peak NAS score (P = 0.04) or head circumference (P = 0.04).” However, two other primary outcomes were significantly better in the buprenorphine group: (1) quantities of morphine used for neonatal abstinence syndrome (NAS) and (2): ‘total hospital stay’. The prognostic significance of these outcomes is unknown to my best knowledge.
The numbers of enrolled subjects were not large enough to show anything but very major outcome effects as being statistically significant. Previous experience has consistently shown only modest differences between methadone and buprenorphine regarding neonatal outcomes. Hence this trial was under-powered on the numbers to find minor differences to statistical significance.
Aside from the unsurprising neonatal outcomes, there were some dramatic and remarkable maternal findings which are mentioned but not brought to the prominence they deserve in my view. These differences are so great that they may even invalidate the neonatal findings (for example if those with high tolerance or rapid metabolism were more likely to drop out).
To my mind the two most important findings of the study are as follows:
The methadone group (n=89) had 16 drop-outs (18%) while the buprenorphine group (n=86) had 28 drop-outs (33%) [p=0.02]. Even more dramatic, of the 16 methadone drop-outs, 2 were due to ‘dissatisfaction with the medication’ while the corresponding number for the buprenorphine candidates was 20, a massive difference. These findings are discussed in the text but should probably also be enshrined in the title of the article. There is no point in having favourable neonatal outcomes if a third of the mothers have left treatment before term.
Even with its failings, I believe that this study provides the most persuasive evidence to date showing the safety and effectiveness of methadone in pregnancy. Indeed, it clearly demonstrates that, in the absence of contraindications, methadone should be the first line drug for opiate dependence in pregnancy (as in the non-pregnant). Yet despite their finding that almost twice as many women dropped out in the buprenorphine group, these authors state, somewhat clumsily: “Although there were no significant differences in overall rates of NAS among infants exposed to buprenorphine and those exposed to methadone, the benefits of buprenorphine in reducing the severity of NAS among neonates with this complication suggest that it should be considered a first-line treatment option in pregnancy.”
Rather than an option, “first line” status implies an obligation in my book. Since buprenorphine is the only alternative medication licensed for opioid dependence then it is obviously an ‘option’, if a somewhat less effective one. This RCT confirms that during pregnancy, consistent with the existing body of research evidence, (pure) buprenorphine should be the second line drug and only used when methadone is found to be clinically inappropriate. I believe that it is unethical to prescribe Suboxone (buprenorphine/naloxone).
Comments by Andrew Byrne ..
http://methadone-research.blogspot.com/
15 December 2010
French study shows torsade rare to vanishing.
Perrin-Terrin A, Pathak A, Lapeyre-Mestre M. QT interval prolongation: prevalence, risk factors and pharmacovigilance data among methadone-treated patients in France. Fundam Clin Pharmacol. 2010 Sep 6;
Dear Colleagues,
These French authors have done our field a great service by replicating Anchersen’s national study from Norway which was so reassuring concerning the use of methadone in addiction treatment.
This study examined QT intervals in a small sample of methadone patients and then compared the results with national reports on adverse events involving methadone and/or cardiac issues including sudden death. These authors found a mean QT interval of 414 ± 29ms with no readings over 500ms, the level at which the risk of arrhythmia is believed to become significant. We are told that analysis of the 42 cases showed that longer QT intervals were associated with recent increases in methadone dose, tobacco smoking, the use of other medications and pre-existing cardiac disease. These findings are consistent with most other work published on this matter, with the notable exception of Wedam. The authors quote QT ‘dispersion’ which is the difference between the shortest and longest QT interval among the twelve leads readings on the standard cardiograph. Despite some initial promise, the significance of ‘dispersion’ has been questioned more recently and its relevance to methadone treatment is uncertain. Even normal values are not agreed upon by cardiologists.
The 550 reports to the official French ‘pharmcovigilence’ centre regarding methadone are of great interest and relevance to the current debate over supposed cardiac effects of methadone. In the ten years to 2007 only 5 reports (0.9%) involved QT problems, three of these with torsade de pointes including one death, a 19 year old who died after unsuccessful resuscitation. This case is not tabulated as having torsade but if he did, as implied in the text, he would represent the first confirmed death from torsade de pointes in the literature to my knowledge.
Over the ten years there were also 7 sudden deaths (1.3%) which the authors tabulate in detail. For some reason they postulate that some or all might be ascribed to arrhythmia. They state: “it is conceivable that serious toxicity might be mediated in part through cardiac effects rather than solely via respiratory depression.” Almost anything is ‘conceivable’ yet the real quesion is whether it is likely or even ‘credible’. In fact the data presented make it highly unlikely that torsade is involved to any significant degree, if at all. Were torsade the cause of just half of these deaths, and considering a reported mortality well under 10% (some say zero) then one would expect hundreds of non-fatal cases of torsade across France - yet only two were ever reported in the whole country over a ten year period. The expected under-reporting in such a voluntary scheme would apply to some extent to both mortality and torsade, even though the latter has become almost ‘notorious’ and was originally described in France and with a French name.
Further, these authors state of several deceased cases: ‘no overdose of methadone’. This is largely based on drug levels found at post-mortem. However, these are now known to be most unreliable alone in determining cause of death. Indeed, serious toxicity and death from narcotism have frequently been found with post-mortem blood methadone in the ‘therapeutic’ range while some patients in normal treatment have levels in or near the toxic range. Also, there are major changes in the levels of measurable methadone following death.
It seemed extraordinary that five of the deceased patients were being treated for psychosis so I wrote to the authors. I have now learned that certain antipsychotics are used commonly in France as alternatives to benzodiazepines, hence not all of these patients were schizophrenic. Each of these 5 patients who were prescribed anti-psychotics died in the first 5 days of methadone maintenance treatment for addiction and two were taking doses which were in excess of current guidelines. Nearly all were receiving four or more prescribed medications apart from the methadone. HIV drugs were involved in two cases. Hence these well-documented deaths also make it clear that polypharmacy is a major factor and the patients would have been self-evident as extremely high risk candidates for treatment.
This study makes it hard to understand the findings of Krantz who found more cases in his own small district than in the whole of France in a decade. Suffice it to say that the findings are even more reassuring than the national figures from Norway published by Anchersen and colleagues.
Comments by Andrew Byrne ..
Related article (includes one of the same authors): Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br. J. Clin. Pharmacol. 2008 66:386–395
In this exhaustive paper using a rational methodology an estimate is made of the incidence of drug induced long QT syndrome (LQTS) at 11 per million per year. The literature shows that over 50% are due to class III antiarrhythmics (presumably in those with existing cardiac rhythm disturbances), closely followed by anti-infective drugs and antihistamines (with presumably some antipsychotics). The drug methadone is not even mentioned in the entire paper so we presume that in 2008 it was not even on the radar for these experienced and thorough researchers. This casts yet further doubt of the contention of Dr Mori Krantz that cardiac problems constitute a public health priority in methadone treatment in America.
Dear Colleagues,
These French authors have done our field a great service by replicating Anchersen’s national study from Norway which was so reassuring concerning the use of methadone in addiction treatment.
This study examined QT intervals in a small sample of methadone patients and then compared the results with national reports on adverse events involving methadone and/or cardiac issues including sudden death. These authors found a mean QT interval of 414 ± 29ms with no readings over 500ms, the level at which the risk of arrhythmia is believed to become significant. We are told that analysis of the 42 cases showed that longer QT intervals were associated with recent increases in methadone dose, tobacco smoking, the use of other medications and pre-existing cardiac disease. These findings are consistent with most other work published on this matter, with the notable exception of Wedam. The authors quote QT ‘dispersion’ which is the difference between the shortest and longest QT interval among the twelve leads readings on the standard cardiograph. Despite some initial promise, the significance of ‘dispersion’ has been questioned more recently and its relevance to methadone treatment is uncertain. Even normal values are not agreed upon by cardiologists.
The 550 reports to the official French ‘pharmcovigilence’ centre regarding methadone are of great interest and relevance to the current debate over supposed cardiac effects of methadone. In the ten years to 2007 only 5 reports (0.9%) involved QT problems, three of these with torsade de pointes including one death, a 19 year old who died after unsuccessful resuscitation. This case is not tabulated as having torsade but if he did, as implied in the text, he would represent the first confirmed death from torsade de pointes in the literature to my knowledge.
Over the ten years there were also 7 sudden deaths (1.3%) which the authors tabulate in detail. For some reason they postulate that some or all might be ascribed to arrhythmia. They state: “it is conceivable that serious toxicity might be mediated in part through cardiac effects rather than solely via respiratory depression.” Almost anything is ‘conceivable’ yet the real quesion is whether it is likely or even ‘credible’. In fact the data presented make it highly unlikely that torsade is involved to any significant degree, if at all. Were torsade the cause of just half of these deaths, and considering a reported mortality well under 10% (some say zero) then one would expect hundreds of non-fatal cases of torsade across France - yet only two were ever reported in the whole country over a ten year period. The expected under-reporting in such a voluntary scheme would apply to some extent to both mortality and torsade, even though the latter has become almost ‘notorious’ and was originally described in France and with a French name.
Further, these authors state of several deceased cases: ‘no overdose of methadone’. This is largely based on drug levels found at post-mortem. However, these are now known to be most unreliable alone in determining cause of death. Indeed, serious toxicity and death from narcotism have frequently been found with post-mortem blood methadone in the ‘therapeutic’ range while some patients in normal treatment have levels in or near the toxic range. Also, there are major changes in the levels of measurable methadone following death.
It seemed extraordinary that five of the deceased patients were being treated for psychosis so I wrote to the authors. I have now learned that certain antipsychotics are used commonly in France as alternatives to benzodiazepines, hence not all of these patients were schizophrenic. Each of these 5 patients who were prescribed anti-psychotics died in the first 5 days of methadone maintenance treatment for addiction and two were taking doses which were in excess of current guidelines. Nearly all were receiving four or more prescribed medications apart from the methadone. HIV drugs were involved in two cases. Hence these well-documented deaths also make it clear that polypharmacy is a major factor and the patients would have been self-evident as extremely high risk candidates for treatment.
This study makes it hard to understand the findings of Krantz who found more cases in his own small district than in the whole of France in a decade. Suffice it to say that the findings are even more reassuring than the national figures from Norway published by Anchersen and colleagues.
Comments by Andrew Byrne ..
Related article (includes one of the same authors): Molokhia M, Pathak A, Lapeyre-Mestre M, et al. Case ascertainment and estimated incidence of drug-induced long-QT syndrome: study in Southwest France. Br. J. Clin. Pharmacol. 2008 66:386–395
In this exhaustive paper using a rational methodology an estimate is made of the incidence of drug induced long QT syndrome (LQTS) at 11 per million per year. The literature shows that over 50% are due to class III antiarrhythmics (presumably in those with existing cardiac rhythm disturbances), closely followed by anti-infective drugs and antihistamines (with presumably some antipsychotics). The drug methadone is not even mentioned in the entire paper so we presume that in 2008 it was not even on the radar for these experienced and thorough researchers. This casts yet further doubt of the contention of Dr Mori Krantz that cardiac problems constitute a public health priority in methadone treatment in America.
14 December 2010
QT changes in babies aged one day uncertain relevance.
Parikh R, Hussain T, Holder G, Bhoyar A, Ewer AK. Maternal methadone therapy increases QTc interval in newborn infants. Arch Dis Child Fetal Neonatal Ed 2010 doi:10.1136/adc.2009.181701
Dear Colleagues,
These authors set out to measure the QT interval in newborns for the first week of life from both ‘uncomplicated’ methadone mothers and ‘healthy’ or drug-free controls. The finding was that there was a small but significant increase on days 1 and 2 (~30ms) which was absent by days 4 and 7. On the first day of life there were 4 of 26 methadone exposed babies with QTc of greater than 500 yet these were all outliers, the 5th longest interval being less than 460ms. By day two only one was near 500ms while later readings were all below these levels. There were no cases of torsade de pointes nor any other rhythm disturbance.
As with other reports, the ability of experts to read QT intervals was limited. The inter-observer and intra-observer variations were given as minus 14 to plus 21ms. Hence it appears that a 30-40 ms difference in QT interval is a rather imprecise figure, since these 95% confidence limits are so wide.
A single case study by these authors in 2007 indicated movement of methadone across the placenta and changes in QT in the newborn, something which is hardly surprising but of unknown clinical significance.
I was not sure whether or not I should bring this to the attention of a wider readership, so slanted is the emphasis of the research and so lacking is it in practical clinical relevance. Ever since the commencement of the campaign to talk up the relevance of QT changes in methadone patients, new and supposedly ever more worrying facets of the problem have been ‘exposed’ - most recently questing whether testosterone levels are the cause! Or that racemic methadone was the problem and levo-methadone the solution (see refs below).
The premise here again seems to be that there are unexplained sudden deaths in methadone patients and their offspring and that a proportion of these may be due to torsade de pointes arrhythmia. Yet such a death has never been reported to my best knowledge. While some still-births or SIDS cases may possibly be due to torsades, the proportion must be extremely low owing to the paucity of reports of non-fatal cases (I could only find one confirmed case from the 1970s and it is reported that torsade mortality is very low or even zero).
Regarding adult cases, despite an aging population with a high rate of other serious illnesses and drug taking, reports of torsade de pointes arrhythmia in methadone patients continue to be sparse indeed. Furthermore, nearly all can be linked to significant risk factors other than (or as well as) the methadone. It is still possible that methadone actually lowers the rate of torsade de pointes - but only large prospective studies could prove that point … and such work would be impractical and expensive (and very probably unethical, considering the proven benefits of methadone treatment both for pregnancy and other outcomes).
Mori Krantz wrote that cardiac safety (in adults) was now a ‘national priority’. The references he used to support his thesis of increasing unexplained deaths in methadone patients (Balesteros; Sorg; Gagajewski; Shah) describe precisely the opposite on my own careful reading (none in Ballesteros; one from Sorg; none in Gagajewski; reducing, not increasing death rates in Shah’s report from New Mexico).
The main issue with the present item is balancing the small risks of methadone in pregnant women with the enormous risks of street heroin to the mother and baby. While a good alternative, buprenorphine is still less effective and technically not approved in pregnancy.
So in this case, as for adult opioid treatment, research energies have been devoted to a problem which is largely theoretical. Equally, we have seen new ‘guidelines’ and recommendations promulgated by health authorities, Colleges, hospitals, etc, each addressing an almost non-existent ‘problem’. One can only speculate at the reasons behind such moves concerning an established, effective drug. The same thing is happening for propoxyphene (Darvon, Digesic, Doloxene) which has just been withdrawn in America based on limited evidence of potential harm. This is against the actual evidence of 50 years of safe and effective use across the world as a second or third line opiate analgesic. According to some authors denigrating old drugs is a time-honoured tactic of drug companies to promote profits derived from more modern, patented and often very expensive drugs. I hasten to state that there is no evidence of this occurring with the current case.
The final line of this abstract says it all: “Bradycardia, tachycardia or an irregular heart rate in an infant born to a mother on methadone treatment should prompt investigation with a 12-lead ECG.” I would be concerned about any baby with an atypical pulse, NOT JUST the babies of mothers taking methadone.
Comments by Andrew Byrne ..
References:
Daniell HW. Does Methadone Prolong QTc Intervals by Depleting Testosterone Levels? Arch Int Med 2010 170;15:1407-8
Ansermot N, Albayrak O, Schlapfer J, et al. Substitution of (R,S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170(6):529-536
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631 NO MOBILE
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I am a deeply religious non-believer - this is a somewhat new kind of religion.
Albert Einstein d.1954. Me too! Andrew Byrne b.1954.
Dear Colleagues,
These authors set out to measure the QT interval in newborns for the first week of life from both ‘uncomplicated’ methadone mothers and ‘healthy’ or drug-free controls. The finding was that there was a small but significant increase on days 1 and 2 (~30ms) which was absent by days 4 and 7. On the first day of life there were 4 of 26 methadone exposed babies with QTc of greater than 500 yet these were all outliers, the 5th longest interval being less than 460ms. By day two only one was near 500ms while later readings were all below these levels. There were no cases of torsade de pointes nor any other rhythm disturbance.
As with other reports, the ability of experts to read QT intervals was limited. The inter-observer and intra-observer variations were given as minus 14 to plus 21ms. Hence it appears that a 30-40 ms difference in QT interval is a rather imprecise figure, since these 95% confidence limits are so wide.
A single case study by these authors in 2007 indicated movement of methadone across the placenta and changes in QT in the newborn, something which is hardly surprising but of unknown clinical significance.
I was not sure whether or not I should bring this to the attention of a wider readership, so slanted is the emphasis of the research and so lacking is it in practical clinical relevance. Ever since the commencement of the campaign to talk up the relevance of QT changes in methadone patients, new and supposedly ever more worrying facets of the problem have been ‘exposed’ - most recently questing whether testosterone levels are the cause! Or that racemic methadone was the problem and levo-methadone the solution (see refs below).
The premise here again seems to be that there are unexplained sudden deaths in methadone patients and their offspring and that a proportion of these may be due to torsade de pointes arrhythmia. Yet such a death has never been reported to my best knowledge. While some still-births or SIDS cases may possibly be due to torsades, the proportion must be extremely low owing to the paucity of reports of non-fatal cases (I could only find one confirmed case from the 1970s and it is reported that torsade mortality is very low or even zero).
Regarding adult cases, despite an aging population with a high rate of other serious illnesses and drug taking, reports of torsade de pointes arrhythmia in methadone patients continue to be sparse indeed. Furthermore, nearly all can be linked to significant risk factors other than (or as well as) the methadone. It is still possible that methadone actually lowers the rate of torsade de pointes - but only large prospective studies could prove that point … and such work would be impractical and expensive (and very probably unethical, considering the proven benefits of methadone treatment both for pregnancy and other outcomes).
Mori Krantz wrote that cardiac safety (in adults) was now a ‘national priority’. The references he used to support his thesis of increasing unexplained deaths in methadone patients (Balesteros; Sorg; Gagajewski; Shah) describe precisely the opposite on my own careful reading (none in Ballesteros; one from Sorg; none in Gagajewski; reducing, not increasing death rates in Shah’s report from New Mexico).
The main issue with the present item is balancing the small risks of methadone in pregnant women with the enormous risks of street heroin to the mother and baby. While a good alternative, buprenorphine is still less effective and technically not approved in pregnancy.
So in this case, as for adult opioid treatment, research energies have been devoted to a problem which is largely theoretical. Equally, we have seen new ‘guidelines’ and recommendations promulgated by health authorities, Colleges, hospitals, etc, each addressing an almost non-existent ‘problem’. One can only speculate at the reasons behind such moves concerning an established, effective drug. The same thing is happening for propoxyphene (Darvon, Digesic, Doloxene) which has just been withdrawn in America based on limited evidence of potential harm. This is against the actual evidence of 50 years of safe and effective use across the world as a second or third line opiate analgesic. According to some authors denigrating old drugs is a time-honoured tactic of drug companies to promote profits derived from more modern, patented and often very expensive drugs. I hasten to state that there is no evidence of this occurring with the current case.
The final line of this abstract says it all: “Bradycardia, tachycardia or an irregular heart rate in an infant born to a mother on methadone treatment should prompt investigation with a 12-lead ECG.” I would be concerned about any baby with an atypical pulse, NOT JUST the babies of mothers taking methadone.
Comments by Andrew Byrne ..
References:
Daniell HW. Does Methadone Prolong QTc Intervals by Depleting Testosterone Levels? Arch Int Med 2010 170;15:1407-8
Ansermot N, Albayrak O, Schlapfer J, et al. Substitution of (R,S)-methadone by (R)-methadone: impact on QTc interval. Arch Intern Med. 2010;170(6):529-536
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
Dr Andrew Byrne MB BS (Syd) FAChAM (RACP)
Dependency Medicine,
75 Redfern Street, Redfern,
New South Wales, 2016, Australia
Email - ajbyrne@ozemail.com.au
Tel (61 - 2) 9319 5524 Fax 9318 0631 NO MOBILE
~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~
I am a deeply religious non-believer - this is a somewhat new kind of religion.
Albert Einstein d.1954. Me too! Andrew Byrne b.1954.
22 October 2010
Three articles addressing problems with buprenorphine treatment.
Dear Colleagues,
Three interesting articles (citations below) have come out recently each addressing a limitation of buprenorphine in clinical practice. Last week’s JAMA has a description of a trial using a depot form of buprenorphine in America. There is also a supporting editorial from Patrick O’Connor from Yale University who points out the restrictions of current opioid treatments and the need for alternatives.
Unsurprisingly, the implant patients had more opiate-free urine tests (40%) than placebo patients (25%) and better retention (60% versus 30%). Just over 50% of the recipients reported significant local reactions at the implant sites, both active and placebo groups but none had to be removed early. One developed frank cellulitis. The blood levels of buprenorphine were found to be in the low range yet it is pointed out that retention rate is about double that of trials of sublingual buprenorphine.
I find it hard to understand how the disadvantages of a fixed dose and surgical insertion of implants could outweigh the high patient acceptability and modest cost of custom dosing of sublingual buprenorphine.
Rather than comparing the buprenorphine 80mg implants with evidence based methadone maintenance treatment (O’Connor calls it the ‘gold standard’ in his editorial) these veteran researchers used placebo implants and ‘rescue’ sub-lingual buprenorphine as a control group. Nor was there any third group for comparison with existing treatments. In my experience this is what is commonly seen in drug company funded trials aimed at marketing approval rather than scientific investigations to determine clinically important questions (see below). O’Connor states that criticism of the use of a placebo group is moderated to some degree by the need for a definitive assessment of a new delivery method and the fact that the placebo group was smaller than the active cohort (55 versus 108) with supplemental sub-lingual buprenorphine available under certain circumstances. While this design may improve the statistical power of the findings, it lowers the credibility of the researchers involved in my view, like the HIV cases in Africa who were denied treatment ‘in the interests of science’. It must be said, sadly, that it is consistent with the much quoted statistic that up to 6 out of 7 American drug addicts are denied appropriate treatment.
The reader is informed that the study was funded by a pharmaceutical company whose personnel collected and monitored data and were involved in the design of the study, management, analysis, and interpretation of the data and preparation, review, and approval of the manuscript. One is left wondering just what the named authors did by comparison with the anonymous ones. The researchers’ financial disclosure statement runs to 33 lines of small print. This may be a record in my own reading.
Another report comes from Malaysia where the combination buprenorphine/naloxone tablet replaced the pure product which was being widely abused, including injecting. While there was a reduction in some harmful behaviour, the focus group reports make fascinating reading. They would appear to confirm James Bell’s finding that the combination product is significantly weaker than the pure product it replaced (a 50% increase was required on average). Malaysian patients here reported the need for double the dose for the same degree of effect when the antagonist was added, despite claims that its absorption is clinically insignificant.
The present researchers, who had previously investigated HIV transmission in Kuala Lumpur, state: “ … the results of the second wave survey suggest a continuing widespread [intravenous use buprenorphine/naloxone], at least in Kuala Lumpur.” “The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.” Some addicts reported that the combination pill was not as desirable.
These findings accord with Robinson’s report from New Zealand 20 years ago when injecting of buprenorphine combination was so prevalent that it was withdrawn from the market completely. They also quote Bruce et al who concluded in 2009 that introduction of combination buprenorphine to Malaysia ‘did not reduce BNX injection or associated risk behaviors’. His group also found that the change to combination buprenorphine was associated with increased quantities injected in about half of the patients interviewed. Their informants also reported that injecting smaller quantities of the combination product or using additives of benzodiazepines or heroin could avoid withdrawal reactions. Paradoxically, the change to a combination drug had made buprenorphine generally less attractive, more expensive and less available to addicts than street heroin in many cases. It is surprising that such a study has not been performed in Australia where both forms of the drug are available and widely used.
The third report is from a group in New York which found high rates of precipitated withdrawal in commencements onto buprenorphine treatment (17%). Such reactions were more common with lower initial doses, recent methadone use and concurrent benzodiazepine use. To her great credit, Dr Whitley reported in 2007 on the co-locating of buprenorphine and methadone treatments. While she called this ‘novel’, for the rest of the world it is just normal. The American legislative requirement to isolate methadone prescribed patients is indeed bizarre and counter-productive.
One problem with the high rate of precipitated withdrawals may have been due to the use of combination product containing the antagonist naloxone. This is contrary to the original American treatment guidelines which advised stabilising patients on pure buprenorphine before transferring to the combination product.
Equivalence studies have still not been performed despite such research being relatively simple and cheap. Furthermore, despite 0.4mg pure product being marketed in Australia for ten years, there is still no low-dose combination product available (eg. 0.4mg or 0.2mg increments for those taking less than, say, 4mg daily). 40 years of experience with methadone have shown that carefully graduated dose reductions are often necessary to achieve abstinence.
It was the low potency preparations, both pure and combination, which became subject to wholesale abuse 20 years ago in New Zealand (Robinson, D&A Dependence 1993 13;1:86). I understand that in America the smallest tablet available is a non-bisectable 2mg pill, making reductions towards abstinence extremely challenging for patient and clinician alike. It would be like the lowest dose of methadone available being around 20mg daily in my estimation. Some ultimately successful abstinence patients have taken very low doses for a long period before eventually ceasing their pharmacotherapy.
Our own practice experience with buprenorphine inductions has been similar to what one might expect from the literature. We have had a very low rate of precipitated withdrawal reactions (<5%) but a failure rate for inductions of approximately 20-40%, mostly due to the drug not abolishing withdrawals. This is about double our failure rate with methadone. Our impression is that there are also excess early dropouts in those successfully inducted onto buprenorphine, as also reported by others.
Personal disclosure: I first prescribed buprenorphine (off-label) in 1986 and have been an enthusiastic supporter of its use for dependency ever since. While methadone is the ‘gold standard’ it does not suit everyone with opioid dependency. For many years our dispensary has had about 20% of our opioid pharmacotherapy patients taking (pure) buprenorphine. I personally do not prescribe the combination product due to the lack of safety and equivalence data as well as a lack of the 0.4mg preparation allowing low-dose titration. Our Concord Dependency Seminar group receives sponsorship for refreshments by Reckitt Benckiser who have also generously donated a data projector.
Comments by Andrew Byrne ..
Full citations:
Ling W, Casadonte P, Bigelow G, Kampman KM, Patkar A, Bailey GL, Rosenthal RN, Beebe KL. Buprenorphine Implants for Treatment of Opioid Dependence A Randomized Controlled Trial. JAMA 2010 304;14:1576-1583
Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC. Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia. Drug and Alcohol Dependence 2010 111;1/2:44-
http://www.ncbi.nlm.nih.gov/pubmed/20478668
Whitley SD, Sohler NL, Kunins HV, Giovanniello A, Li X, Sacajiu G, Cunningham CO. Factors associated with complicated buprenorphine inductions. J Subst Abuse Treat. 2010 39;1:51-57
Three interesting articles (citations below) have come out recently each addressing a limitation of buprenorphine in clinical practice. Last week’s JAMA has a description of a trial using a depot form of buprenorphine in America. There is also a supporting editorial from Patrick O’Connor from Yale University who points out the restrictions of current opioid treatments and the need for alternatives.
Unsurprisingly, the implant patients had more opiate-free urine tests (40%) than placebo patients (25%) and better retention (60% versus 30%). Just over 50% of the recipients reported significant local reactions at the implant sites, both active and placebo groups but none had to be removed early. One developed frank cellulitis. The blood levels of buprenorphine were found to be in the low range yet it is pointed out that retention rate is about double that of trials of sublingual buprenorphine.
I find it hard to understand how the disadvantages of a fixed dose and surgical insertion of implants could outweigh the high patient acceptability and modest cost of custom dosing of sublingual buprenorphine.
Rather than comparing the buprenorphine 80mg implants with evidence based methadone maintenance treatment (O’Connor calls it the ‘gold standard’ in his editorial) these veteran researchers used placebo implants and ‘rescue’ sub-lingual buprenorphine as a control group. Nor was there any third group for comparison with existing treatments. In my experience this is what is commonly seen in drug company funded trials aimed at marketing approval rather than scientific investigations to determine clinically important questions (see below). O’Connor states that criticism of the use of a placebo group is moderated to some degree by the need for a definitive assessment of a new delivery method and the fact that the placebo group was smaller than the active cohort (55 versus 108) with supplemental sub-lingual buprenorphine available under certain circumstances. While this design may improve the statistical power of the findings, it lowers the credibility of the researchers involved in my view, like the HIV cases in Africa who were denied treatment ‘in the interests of science’. It must be said, sadly, that it is consistent with the much quoted statistic that up to 6 out of 7 American drug addicts are denied appropriate treatment.
The reader is informed that the study was funded by a pharmaceutical company whose personnel collected and monitored data and were involved in the design of the study, management, analysis, and interpretation of the data and preparation, review, and approval of the manuscript. One is left wondering just what the named authors did by comparison with the anonymous ones. The researchers’ financial disclosure statement runs to 33 lines of small print. This may be a record in my own reading.
Another report comes from Malaysia where the combination buprenorphine/naloxone tablet replaced the pure product which was being widely abused, including injecting. While there was a reduction in some harmful behaviour, the focus group reports make fascinating reading. They would appear to confirm James Bell’s finding that the combination product is significantly weaker than the pure product it replaced (a 50% increase was required on average). Malaysian patients here reported the need for double the dose for the same degree of effect when the antagonist was added, despite claims that its absorption is clinically insignificant.
The present researchers, who had previously investigated HIV transmission in Kuala Lumpur, state: “ … the results of the second wave survey suggest a continuing widespread [intravenous use buprenorphine/naloxone], at least in Kuala Lumpur.” “The introduction of BNX and withdrawal of BUP may have helped to reduce, but did not eliminate the problems with diversion and abuse.” Some addicts reported that the combination pill was not as desirable.
These findings accord with Robinson’s report from New Zealand 20 years ago when injecting of buprenorphine combination was so prevalent that it was withdrawn from the market completely. They also quote Bruce et al who concluded in 2009 that introduction of combination buprenorphine to Malaysia ‘did not reduce BNX injection or associated risk behaviors’. His group also found that the change to combination buprenorphine was associated with increased quantities injected in about half of the patients interviewed. Their informants also reported that injecting smaller quantities of the combination product or using additives of benzodiazepines or heroin could avoid withdrawal reactions. Paradoxically, the change to a combination drug had made buprenorphine generally less attractive, more expensive and less available to addicts than street heroin in many cases. It is surprising that such a study has not been performed in Australia where both forms of the drug are available and widely used.
The third report is from a group in New York which found high rates of precipitated withdrawal in commencements onto buprenorphine treatment (17%). Such reactions were more common with lower initial doses, recent methadone use and concurrent benzodiazepine use. To her great credit, Dr Whitley reported in 2007 on the co-locating of buprenorphine and methadone treatments. While she called this ‘novel’, for the rest of the world it is just normal. The American legislative requirement to isolate methadone prescribed patients is indeed bizarre and counter-productive.
One problem with the high rate of precipitated withdrawals may have been due to the use of combination product containing the antagonist naloxone. This is contrary to the original American treatment guidelines which advised stabilising patients on pure buprenorphine before transferring to the combination product.
Equivalence studies have still not been performed despite such research being relatively simple and cheap. Furthermore, despite 0.4mg pure product being marketed in Australia for ten years, there is still no low-dose combination product available (eg. 0.4mg or 0.2mg increments for those taking less than, say, 4mg daily). 40 years of experience with methadone have shown that carefully graduated dose reductions are often necessary to achieve abstinence.
It was the low potency preparations, both pure and combination, which became subject to wholesale abuse 20 years ago in New Zealand (Robinson, D&A Dependence 1993 13;1:86). I understand that in America the smallest tablet available is a non-bisectable 2mg pill, making reductions towards abstinence extremely challenging for patient and clinician alike. It would be like the lowest dose of methadone available being around 20mg daily in my estimation. Some ultimately successful abstinence patients have taken very low doses for a long period before eventually ceasing their pharmacotherapy.
Our own practice experience with buprenorphine inductions has been similar to what one might expect from the literature. We have had a very low rate of precipitated withdrawal reactions (<5%) but a failure rate for inductions of approximately 20-40%, mostly due to the drug not abolishing withdrawals. This is about double our failure rate with methadone. Our impression is that there are also excess early dropouts in those successfully inducted onto buprenorphine, as also reported by others.
Personal disclosure: I first prescribed buprenorphine (off-label) in 1986 and have been an enthusiastic supporter of its use for dependency ever since. While methadone is the ‘gold standard’ it does not suit everyone with opioid dependency. For many years our dispensary has had about 20% of our opioid pharmacotherapy patients taking (pure) buprenorphine. I personally do not prescribe the combination product due to the lack of safety and equivalence data as well as a lack of the 0.4mg preparation allowing low-dose titration. Our Concord Dependency Seminar group receives sponsorship for refreshments by Reckitt Benckiser who have also generously donated a data projector.
Comments by Andrew Byrne ..
Full citations:
Ling W, Casadonte P, Bigelow G, Kampman KM, Patkar A, Bailey GL, Rosenthal RN, Beebe KL. Buprenorphine Implants for Treatment of Opioid Dependence A Randomized Controlled Trial. JAMA 2010 304;14:1576-1583
Vicknasingam B, Mazlan M, Schottenfeld RS, Chawarski MC. Injection of buprenorphine and buprenorphine/naloxone tablets in Malaysia. Drug and Alcohol Dependence 2010 111;1/2:44-
http://www.ncbi.nlm.nih.gov/pubmed/20478668
Whitley SD, Sohler NL, Kunins HV, Giovanniello A, Li X, Sacajiu G, Cunningham CO. Factors associated with complicated buprenorphine inductions. J Subst Abuse Treat. 2010 39;1:51-57
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