Noble attempt to tease out role of dose supervision in OTP.

Holland R, Maskrey V, Swift L, Notley C, Robinson A, Nagar J, Gale T, Kouimtsidis C. Treatment retention, drug use and social functioning outcomes in those receiving 3 months versus 1 month of supervised opioid maintenance treatment. Results from the Super C randomized controlled trial. Addiction 2014 109;4:596-604 

 

Summary: Dose supervision is the last frontier of our OTP evidence base.  All seem agreed with early supervised induction doses yet there are very different views on the use of unsupervised (take-home/take-away) doses and when these can safely be introduced.  The UK has commonly used unsupervised methadone while America and France introduced unsupervised buprenorphine despite virtually no research on these protocols (Fudala used supervision for most of his trial).   This second attempt should not deter these authors from trying again, perhaps using some international input. 

 

Dear Colleagues, 

 

These authors assessed 627 patients entering opioid maintenance treatment of whom 32% were deemed to need daily, supervised doses and 5% were deemed to need (or ‘deserve’?) unsupervised dosing.  Another ~15% were excluded for other reasons, leaving 298 subjects who were randomised to 3 months daily supervised dosing or daily dose collection with self administration, at the clinician's discretion after the first month of daily supervised dosing.  The primary outcome was retention at 3 months which showed no significant difference (74% in the un-supervised group versus 60%).  By 6 months the retention was within 1% for the two groups, approximately 55% a finding which is in keeping with other reports (Bell 2006).   Nor were any differences found in illicit opioid use. 

 

Some ‘trends’ here seemed to run contrary to a pilot study in Scotland by the same first author yet these differences are not addressed directly although another study from Italy is quoted as being consistent in some respects.  It would be a spurious to conclude that ‘no significant difference’ proves ‘supervision is unnecessary’ until or unless a larger and more rigorous study were conducted. 

 

Unfortunately, like much research from the UK (notably the NTORS ‘study’) this trial provides little information for clinicians giving opioid maintenance.  The authors take a form of treatment which is used around the world (supervised daily initiation) and then compare it with a home-grown practice of daily attendance for dispensed doses to take home for unsupervised consumption.   This protocol also prevents a valid comparison with other studies comparing varying numbers of dispensed doses each week (see Rhoades et al. who examined 2 versus 5 dispensed doses weekly on two dose levels). 

 

The authors state that supervised dispensing is more costly than non-supervised, without any references.  Our own experience is that it is cheaper, simpler and faster to give a supervised dose at the counter than to make up a bottle, seal it with a child resistant lid, label it and place it into a suitable bag for the patient to take away.  They state further that the practice of supervised consumption implies a lack of trust yet there is a trend for supervised consumption of medication in many other fields of medicine, mostly with positive outcomes (eg. malaria, TB, HIV, vaccinations, STD, UTI).  The question of ‘trust’ might equally well be posed in the reverse: can the patient ‘trust’ the doctor to prescribe in the most effective manner?  Unsupervised treatment is simply not evidence-based in the addiction area.  

 

Some parts of the UK have poor quality maintenance treatments: very little methadone was supervised and doses were often grossly inadequate (mean 37mg daily in 1999 according to J. Strang and Sheridan).  It should therefore be of no surprise that there is a vigorous market locally for illicit opioid including methadone (more than one third of these subjects reported the use of illicit methadone on entering treatment).  Furthermore OTP in the UK has a poor ‘image’ it would appear. 

 

This study by Holland et al. excluded fully half the possible subjects based on whether the clinician believed the patient did or did not need supervised dosing, the very subject which the researchers are trying to test.  It makes rather a mess of the thesis being examined … yet this subject is serious and worthy of debating and research which has been sorely lacking to date. 

 

The authors point out that the data were collected by existing staff which may introduce a favour bias.  Many UK clinicians defend unsupervised treatment yet there is still no controlled research to demonstrate its safety and effectiveness (and much to indicate that opioid maintenance in the UK is a disaster with the government effectively trying to ban all but reduction treatment programs if my reading is correct).  I believe that as with Rhoades work, the effort should be to carefully examine the use of extended take-home protocols and examine the numerous outcome measures.  Of course one cannot perform a double blind trial of two such physically different interventions. 

 

In America over the past ten years a national guideline (not evidence based in my view) has allowed many patients to take 4 weeks supply of methadone (one supervised dose plus 27 take-home bottles) even after a relatively short period of documented stability.  Yet I could find no published research on this ‘noble experiment’ apart from the very old monthly maintenance trial at Beth Israel, New York (Novick et al.) which mostly had positive results. 

 

Holland et al. discuss an apparently significant finding in their data whereby unsupervised patients seem to be involved in less crime.  However, they to not canvass the possibility that those receiving unsupervised methadone may have less financial pressure if selling a proportion of their medication.  When I contacted the authors I was told this was a possibility despite denials of diversion in patient questionnaires.  The mean daily dose (sent to my kindly by the first author) at 58mg is in fact less than the minimum effective dose for the majority of patients as quoted by Strang’s group at 60mg daily.  They advised 60-120mg daily for most opiate dependent patients.  The dose level of buprenorphine was much the same as elsewhere at 10.5mg daily (for which I thank Dr Holland).  Vincent Dole, whose group originally devised methadone maintenance treatment in New York, stated that with appropriate treatment illicit opiate use should be eliminated in 90% of dependent individuals.  But this requires sufficient psychosocial support, adequate doses and some degree of supervision. 

 

The elephant in the room on this subject, not addressed by these authors, is public perception.  It is far easier to justify a program which supervises methadone doses for a population who, by definition, have lost some control over their drug use.  As these authors state at the start of their article: “Supervision ensures that patients take their medication as prescribed and prevents illicit drug diversion [sic].” Daily supervised treatment (often with one take-home dose for Sunday) is the proven standard for treatment induction, as long as there is no contraindication (homelessness, actively using family members, current psychosis, acute concurrent alcoholism, etc where even Sunday supervision is advised where possible). 

 

As in other fields of medicine all decisions should be reviewed in light of the patient’s response to treatment, in this case, judged by attendance, self-report, physical examination of veins, pupils, etc and urine or blood testing.  Most patients can be successfully treated by second or third daily attendance within the first year in our experience (meaning 3 to 5 take-home doses weekly).  Increased supervision occasionally has to be reintroduced if the clinician and or the patient finds their control is again being lost.  Others can move to less frequent attendance before leaving treatment after sufficient time on reducing dose schedules when this is tolerated. 

 

Another ‘canard’ is prison entry.  For an inmate on supervised treatment a dose, any dose level can confidently be administered on receipt of written confirmation of last-dose and ID information from the community pharmacy or clinic.  For non-supervised patients however, prison medical staff are obliged to follow induction protocols in the case of a patient who might not be taking all of their daily doses.  In such a case even a single dose could be fatal (~70mg is considered a lethal dose in non-dependent adults where the average dose on most well run programs is higher than this). 

 

 

Comments by Andrew Byrne ..

 

Declaration of potential conflict of interest: Dr Byrne’s clinic charges a fee for supervising the administration of methadone and buprenorphine. 

 

References:

 

Holland R, Matheson C, Anthony G, Roberts K, Priyardarshi S, Macrae A, Whitelaw E, Appavoo S, Bond C. A pilot randomised controlled trial of brief versus twice weekly versus standard supervised consumption in patients on opiate maintenance treatment. D&A Rev 2012 6:483-91

 

Strang J, Sheridan J, Hunt C, Kerr B, Gerada C, Pringle M. The prescribing of methadone and other opioids to addicts: national survey of GPs in England and Wales. Brit J General Practice 2005 55;515: 444-451

 

Rhoades HM, Creson D, Elk R, Schmitz J, Grabowski J.  Retention, HIV Risk, and Illicit Drug Use during Treatment: Methadone Dose and Visit Frequency. 1998 Am J Public Health 88:34-39

 

Novick DM, Joseph H, Salsitz EA, Kalin MF, Keefe JB, Miller EL, Richman BL. Outcomes of Treatment of Socially Rehabilitated Methadone Maintenance Patients in Physician's Offices (Medical Maintenance). J Gen Intern Med. 1994 9:127-30

 

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins J, Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

 

Drug Misuse and Dependence - Guidelines on Clinical Management. (1999) HMSO Department of Health. Working Group Chair: Strang J.

 

Poor retention buprenorphine/nxn vs. methadone. Also NYT article on bupe.

Hser YI, Saxon AJ … Ling W. Treatment Retention among Patients Randomized to Buprenorphine/Naloxone Compared to Methadone in A Multi-site Trial. Addiction. 2013 Aug 20

 

Dear Colleagues,

 

Over 1000 opiate dependent patients were randomised to methadone or Suboxone and then followed for 24 weeks.  Retention in the methadone group was 74% compared with 46% (p<.01) for those taking buprenorphine with naloxone.  The buprenorphine retention was so poor, more than half dropping out, that they had to recruit more subjects to allow a meaningful comparison of liver function tests, the primary purpose of this Phase IV study (see ref 1 for original report).  There were 24 cases of extreme elevations of liver enzymes but reassuringly, no difference between the groups.  There was no discussion of harm reduction measures since American doctors are banned from such interventions so that harm maximisation can co-exist with an ‘ethical’ trial.  Seroconversions among treated individuals in the community should be exceptional even with the most rudimentary public health services.  Men did better on buprenorphine for some reason. 

 

While the authors say that the retention rates are ‘in the range’ of other studies, the low buprenorphine retention rate would seem to be well out of step with the several RCTs comparing pure buprenorphine with methadone, each finding either no difference or a modest difference between the groups (see Cochrane summary on the subject - ref 2, also refs 3, 4 and 5).  To my reading none found such a substantial difference in retention.  The present authors make the rather hopeful speculation that doses higher than 32mg daily might improve the poor retention rates, despite the basic pharmacology being against this (not to mention the undignified dosing and enormous cost, as well as the fact that most had dropped out long before such doses were achieved).  Inadequate induction protocols might also apply to methadone.  And without routine supervised doses in America, induction in community treatment with buprenorphine in America is hard to determine. 

 

Another possible explanation for the poor results on combination buprenorphine might be that the added naloxone reduced the efficacy of buprenorphine, something which has not been formally tested to my knowledge.  Most RCT have involved pure buprenorphine, including the recent MOTHER study (with all its faults).  There is still no cogent evidence for the thesis that the combination reduces abuse, despite the attractiveness of the concept empirically (ref 6 and see Wiki quote at ref 8). 

 

The possibility that adding naloxone changes the characteristics of buprenorphine is supported by a small but well conducted pilot study from Sydney, funded by the NSW Health Department.  Bell et al. transferred 17 stable (pure) buprenorphine patients to the combination formulation, finding that most needed a higher dose with a mean of just over 50% of the original dose (ref 7). 

 

This present trial was not blinded and we are not informed how patients attending clinics were consented and randomised.  It is possible that incentives such as free treatment might have induced previously successful methadone patients to take a chance on buprenorphine, causing a falsely high drop-out rate for buprenorphine.  However, until there is a valid comparison of pure buprenorphine with the combination product we are forced to rely on indirect evidence and imperfect studies, few if any of which support the use of combination buprenorphine.  Today’s New York Times quotes of the US FDA: “Early this year, it [FDA] approved generic tablets and asked the Federal Trade Commission to investigate potentially anticompetitive business practices by the company.” See link below for very wide-ranging article on buprenorphine. 

 

I still find no cogent reason to use combination buprenorphine.  It is possible that large numbers of opiate dependent patients in Australia and elsewhere are taking naloxone for reasons which are more related to good marketing than good medicine.  I remain a fervent supporter of (pure) buprenorphine as a maintenance treatment and would recommend it as an excellent alternative to methadone with some major benefits as well as some shortcomings. 

 

Written by Andrew Byrne ..

 

STOP PRESS – I highly recommend this detailed front page item in the New York Times http://www.nytimes.com/2013/11/17/health/in-demand-in-clinics-and-on-the-street-bupe-can-be-savior-or-menace.html?partner=rss&emc=rss&_r=0  They still omit the ‘elephant in the room’ which is clinic-type treatment.  Monthly dispensed pills without some structure (counselling, urine testing and/or supervised doses etc) have never been shown to be safe or effective yet that is exactly what many French and American patients receive.  

 

References:

 

1. Saxon AJ, Ling W, Hillhouse M, Thomas C, Hasson A, Ang A, Doraimani G, Tasissa G, Lokhnygina Y, Leimberger J, Bruce RD, McCarthy J, Wiest K, McLaughlin P, Bilangi R, Cohen A, Woody G, Jacobs P. Buprenorphine/Naloxone and methadone effects on laboratory indices of liver health: A randomized trial. Drug Alcohol Depend 2013;128:71-76

 

2. Mattick RP, Kimber J, Breen C, Davoli M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev. 2008 Apr 16;(2):CD002207

 

3. Schottenfeld RS, Pakes JR, Olivento A, Kosten TR, Zeidonis D. Buprenorphine vs Methadone Maintenance Treatment for Concurrent Opioid Dependence and Cocaine Abuse. Arch Gen Psychiatry. 1997 54:713-720

 

4. Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in Buprenorphine- versus methadone-maintained patients. J Nerv Ment Dis. 1998 186;1:35-43

 

5. Pani PP, Maremmani I, Pirastu R, Tagliamonte A, Gessa GL. Buprenorphine: a controlled clinical trial in the treatment of opioid dependence. Drug Alcohol Depend. 2000 60;1:39-50

 

6. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Am J Drug Alcohol Abuse 2009 Feb 12:1

 

7. Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

8. Wiki page on buprenorphine excerpt: http://en.wikipedia.org/wiki/Buprenorphine
"There is a common misconception that naloxone, a potent opioid antagonist included in the Suboxone formulation, is active and responsible for this blockade effect. This is not true. Instead, Buprenorphine alone is responsible for the blockade effect due to its high binding affinity at the brains opioid receptors, a higher affinity than that of naloxone. The naloxone is in effect not active regardless of the route of administration."

  

Should drug companies try to 'tamper-proof' their products? Tactics, profits and ethics may clash.

Summary: Andrew Byrne argues that doctors should not change prescribing practices unless there is substantial evidence regarding safety and effectiveness.  He gives numerous examples where drug companies have got it wrong in the past, sometimes grievously.  He finds that evidence is still lacking for combined buprenorphine preparations over their highly effective and safe (pure) predecessors. 

 

Dear Colleagues,

 

A recent New York Times report states that the FDA has rejected a petition by the original manufacturer of a so-called ‘tamper resistant’ version of oxymorphone analgesic to stop generic competitors being licensed because they were alleged to be less safe than the original product.  The claim by the originators to have a ‘tamper-resistant’ product was rejected by the FDA as the tablets were found to be able to be ‘misused by cutting, grinding, chewing or injecting’.  For yet another long acting opioid a similar recent FDA petition was accepted since the drug, OxyContin “appeared to be less prone to abuse”.  This report was in the NYT ‘business’ section rather than under ‘health’ … and it ends with stock movements following the FDA decisions. http://www.nytimes.com/2013/05/11/business/endo-loses-bid-to-block-sales-of-generic-painkiller.html?src=rechp&_r=0 ). 

 

In another recent ruling, the FDA refused a petition by Reckitt Benckiser, Inc to prevent the approval of generic buprenorphine tablets combined with naloxone due to their alleged dangers to children.  The determination also stated: “The timing of Reckitt’s September 2012 announcement that it would discontinue marketing of the tablet product because of pediatric exposure issues, given its close alignment with the period in which generic competition for this product was expected to begin, cannot be ignored.” (page 15; http://www.regulations.gov/#!documentDetail;D=FDA-2012-P-1028-0011).  

 

 

These complex stories raise the question of whether drug companies and regulatory authorities are capable of regulating the use of a drug beyond its recommended indication and route of administration.  Preventing the inappropriate use of medication is indeed a difficult field and some might say impossible.  The introduction of long acting forms of opioid, including morphine, which are supposedly safer, also coincided with the onset of the present enormous epidemic of analgesic opioid abuse in America and elsewhere. 

 

Certain supposed safety innovations have ended up being more harmful than the original (eg. the altered gel-caps of triazolam (ref 1) which caused serious embolic disease among injectors - one theory was that heating the gel allowed it to dissolve, only to re-precipitate in the body, causing embolic disease).  Drug companies have a potential conflict of interest in that alterations in the formulation of a drug may allow a new patent to be issued, ensuring more profits and locking out competition.  This occurs whether the changes prove effective or not (see above).  Such patents may be perfectly in order yet examples are few in my experience and with each benefit there may be a corresponding ‘sense of security’, ensuing increased prescribing and potentially more harms overall.  Extending patents also raises prices so that many legitimate recipients, even in advanced western countries, may be denied appropriate treatment  (eg. buprenorphine in some parts of the UK).  Another conundrum is that in many advanced countries injectable opioids, including heroin, are now made available for addiction treatment in certain cases. 

 

One early attempt to avoid codeine addiction in Australia employed over-the-counter mixed analgesics such as Vincent’s, ‘Bex’ and APC powders.  They were marketed widely to the public, causing a creeping epidemic of kidney failure, largely in women, 10 to 20 years later.  These mixed analgesics were advertised prominently to the public and large profits were made as people unknowingly suffered slow and irreversible renal damage. 

 

In the case of mixed analgesics, each of the constituents, aspirin, phenacetin, codeine and/or caffeine were arguably in the patients’ medical interests.  In recent times, we find drug companies adding compounds which are of no therapeutic benefit to the individual patient, but are alleged to prevent third-party or unsanctioned abuse (eg. injecting). 

 

Can we be certain that naloxone and buprenorphine is a safe combination?  We were told by the company representatives and senior professional colleagues that the naloxone was not absorbed significantly.  Yet good quality research available long before the drug’s approval would seem to contradict this (ref 2). 

 

We were also told, mostly by senior medical colleagues, that the two approved versions of the drug (pure and combination) were clinically equivalent yet there are no formal comparative trials to my knowledge (and the company now emphasises absorption differences between some of their formulations).  One comparative pilot study with a chronological control indicated the need for substantially higher doses (~50%) when naloxone was added to patients who had been stabilised using pure buprenorphine (ref 3).  Such a finding, if confirmed, would imply substantially increased cost per patient to government, insurance companies and/or the individual patients while at the same time more sales and profits for the manufacturer.  It also implies the consumption of enormous quantities of naloxone by patients who have no requirement for the drug. 

 

Even after decades of experience with the combination products, I can still find no consistent evidence showing any net benefits to balance these increased costs.  There is legion evidence that the combination product can be injected with impunity and gusto by patients and others, despite the good intentions of the manufacturer, prescribers, authorities, etc.  A modest reduction in injecting in New Zealand after national substitution of the pure drug with a combination product in 1992 was cancelled out to some extent by a reported increase in the use of injected morphine (ref 4). 

 

Analgesic buprenorphine was reportedly the leading drug of abuse in several western countries for some years in the 1990s (eg. Spain and New Zealand).  While the financial incentives are obvious, from a public health viewpoint this is a largely uncharted nexus between illicit drug markets and pharmaceuticals for non-medical purposes.  It is hard to believe that the manufacturers were unaware that they were underwriting a large heroin substitution enterprise in those days. 

 

On no less than two occasions, when nearing the end of its patent (or exclusive marketing) period, existing and familiar forms of buprenorphine were suddenly found to have serious problems, ‘requiring’ us to change our prescribing habits to the new versions … and this despite apparently satisfactory results in community practice with pure buprenorphine tablets, and a very low level of adverse events.  So the major advance of the introduction of buprenorphine for opioid dependency was marred by two major disruptions for questionable reasons.  From the patients’ point of view, even when changing brands of a drug, colours or flavours of existing medications, some may experience major torment and even drop out of treatment (ref 5). 

 

After lavish drug launches in Sydney and other capitals in 2006 and 2011 (see my only two food reviews on the research web site) and high profile professional and government support, our colleagues changed their prescribing habits promptly en masse.  In France, where buprenorphine (pure) has been used widely since 1995, moves to combination product were stayed as generic versions of the pure buprenorphine had made major inroads into the market years ago (apparently an Australian company, Sigma-Arrow, was a major player). 

 

Two claims by the manufacturer would seem to be little more than ruses, a contention which is supported by delightfully restrained language in the FDA findings and from abundant anecdotal reports available on the internet plus clinical experience.  We were told by company representatives in Australia that the Suboxone tablets are being withdrawn due to paediatric exposure … something which has only been reported on any scale in America and where tablets are inexplicably sold in bottles of loose pills rather than child resistant blister packs.  The FDA finding reported that by the time of this Reckitt announcement (1) the number of exposures was already dropping in response to existing measures, and (2) in the only quantitated report (n=131), the great majority of exposures were of one tablet or less (2mg to 8mg).  The FDA report did not mention any morbidity or mortality from childhood exposure to buprenorphine despite the theoretical possibility of respiratory depression and death, even from these modest doses (hopefully not combined with alcohol or other drugs). 

 

Another claim was that the new ‘films’ or ‘strips’ would be substantially faster to administer yet this is hard to demonstrate in practice.  Furthermore it is less relevant in America where dose supervision is not used to any degree.  Australian pharmacists and nurses I have spoken to say that the films take longer to give out than the previous tablet forms, and this may not be made up in less time for dissolution of the medication.  In my experience only a proportion of drug administration episodes involve full inspection from buccal insertion to dissolution, with exceptions in the prison system and some well staffed specialist clinics.  The highly soluble films may be easier to abuse but this seems not to have been tested (except by some of our more enterprising patients). 

 

Further to these changes, and without any notice or discussion, in early 2013 the company introduced new packaging for the pure form, Subutex.  It is hard to find any logical reason for this except to make it more difficult to use in replacing a perfectly satisfactory and familiar blister pack.  Subutex is the form which should be used in pregnancy or in those likely to become pregnant.  It is also the only form which is available in 0.4mg increment, a size we find essential in reductions for about a third of our patients, especially on their final reductions to abstinence (a sceptic might think that the company was not interested in abstinence).  The new Subutex packets are very cumbersome, requiring a new skill as well as sharp finger-nails and/or implements to separate the tablet compartments and then extract their contents, a two-step process.  And this in a country with few if any reports of paediatric exposure as far as I am aware.  On behalf of our nurses and pharmacists I have asked the company representative to reconsider and return to the old ‘friendly’ blister packs (to no avail to date). 

 

 

For those who still feel confident with all the information they receive from drug companies I would remind:

 

(a) Heroin was invented by the Bayer company and marketed as a ‘calmative’ for babies and a non-addictive treatment for morphine addiction [sic]. 

 

(b) Thalidomide was reportedly not withdrawn directly in all countries in which it was marketed, even after the publication in Lancet of Dr William McBride’s seemingly unanswerable report in December 1961 (ref 6). 

 

(c) The early lipid lowering agent Clofibrate (“Atromid-S”) was supposed to prevent heart attacks but was reportedly found to cause an increase in strokes.  This was only detected after the company marketed the product for a substantial period during which many patients had received little or no net benefit from the medication. 

 

(d) Reserpine was an early treatment for hypertension which was used less and less due to side effects such as depression (despite the drug at one stage, like benzodiazepines, being used as a depression treatment). 

 

(e) “Halcion” (triazolem), once a big selling sleeping medication in the UK, is quoted as follows: “Clinical trials which Upjohn had withheld from publishing showed a very unfavourable risk benefit ratio with 9.9% of patients dropping out of one triazolam study versus 1.9% of trial subjects taking a comparison benzodiazepine, flurazepam. Another study not published by Upjohn found 12.2% of triazolam patients dropped out, again due to psychiatric adverse effects compared against 4.1% for flurazepam. A further study found that after only 3 weeks use of triazolam patients typically became markedly anxious. As a result of these studies, both published and unpublished, coming to light showing frequent severe psychiatric disturbances the United Kingdom and Brazil decided to ban triazolam.” (Wikipedia).  The company’s choice of name says a lot about their tactics/antics. 

 

The list goes on. 

 

In my view doctors should beware of getting all their information about new drugs from drug company sources but seek independent information on all therapeutic matters, even knowing that medical journals, universities and even Royal Colleges take funding from drug companies.  It is my view that we should be very wary of sample packs (not available for controlled drugs!).  These are so often provided only for preparations which are new, expensive treatments, and which conservative doctors might consider second-line.  In my view, short of a major breakthrough, these should generally be reserved for those who do not do well with existing standard, safe treatments.  If this rule were followed by more doctors some of the disasters of the past might have been avoided. 

 

Despite the above serious reservations about marketing, I respect the pharmaceutical industry as being there to make profits for its shareholders in devising new drugs and bringing them to market.  We all benefit from the great advances of such endeavours. 

 

Written by Andrew Byrne ..

 

Ref 1: Ruben S, Morrison CL. Temazepam misuse in a group of injecting drug users. Br J Addict 1992 87:1387–92

 

Ref 2: Preston KL, Bigelow GE, Liebson IA. Effects of sublingually given naloxone in opioid-dependent human volunteers. Drug and Alcohol Dependence (1990) 25:27-34

 

Ref 2: Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev 2004 23;3:311-318

 

Ref 4: Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence 1993 33;1:81-6

 

Ref 5: Byrne A, Hallinan R, Love A. Administration of a lighter-coloured methadone liquid. D&A Review (2002) 21;4:405

 

Ref 6: McBride WG. Thalidomide and Congenital Abnormalities. Lancet 1961 2:1358

 

 

These are a few items which relate to this theme.  Some are rigorous studies, others just anecdotal or opinion pieces which I leave the reader to judge. 

 

 

Lack of Reduction in Buprenorphine Injection After Introduction of Co-Formulated Buprenorphine/Naloxone to the Malaysian Market. Bruce RD, Govindasamy S, Sylla L, Kamarulzaman A, Altice FL. Am J Drug Alcohol Abuse 2009 Feb 12:1

 

Big Pharma Company Jacks Up Price of Overdose Life Saver by 1100%: Now, More People Will Die.             http://www.alternet.org/big-pharma-company-jacks-price-overdose-life-saver-1100-now-more-people-will-die?akid=10303.1120210.FX4JwZ&rd=1&src=newsletter821675&t=5&paging=off

 

Anaphylaxis After the Injection of Buprenorphine. Boggs CL, Ripple MG, Ali Z, Brassell M, Levine B, Jufer-Phipps R, Doyon S, Fowler DR. J Forensic Sci. 2013 Mar 29

 

Britain Accuses Glaxo of Paying Rivals for Delay of Generic Antidepressant Stephen Castle.  New York Times 20 April

 

Making medicines evergreen. Another loophole exploited by the drug industry. Brunet MD. BMJ 2013; 346 doi: http://dx.doi.org/10.1136/bmj.f354 (Published 22 January 2013)

 

Acute hepatitis and renal failure related to intranasal buprenorphine misuse: case report and literature analysis. Eiden C, Ripault M-P, Peyriere H, Larrey D. Conference presentation. Société Française de Pharmacologie et de Thérapeutique. 8th Congress Angers April 2013

 

Suboxone Misuse Along the Opiate Maintenance Treatment Pathway. Furst RT. J Addict Disease 2012 32;1:53-67

 

Hansen H, Roberts SK. Emerald Book Chapter: Two Tiers of Biomedicalization: Methadone, Buprenorphine, and the Racial Politics of Addiction Treatment. Advances in Medical Sociology 2012 14:79-102

 

Hansen H, Skinner ME. From white bullets to black markets and greened medicine: The neuroeconomics and neuroracial politics of opioid pharmaceuticals. Annals of Anthropological Practice 36.1 167-182

 

Hitchings AW, Baker EH, Khong TK. Making medicines evergreen. BMJ 2012 345:e7941 http://www.bmj.com/content/345/bmj.e7941

 

Peles E, Schreiber S, Adelson M. Opiate-Dependent Patients on a Waiting List for Methadone Maintenance Treatment Are at High Risk for Mortality Until Treatment Entry. J Addict Med 2013 Mar 20. [Epub ahead of print]

 

Reindeerspotting. A Finnish documentary film. The film focuses on a drug addict whose drug of choice is Subutex taken intravenously. He is unemployed and he finances his addiction through thefts, burglaries, and welfare payments.

 

Schwartz RP et al.  Opioid Agonist Treatments and Heroin Overdose Deaths in Baltimore, Maryland, 1995–2009.  March 14, 2013 American Journal of Public Health

 

Winstock AR, Lea T, Sheridan J. Prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid treatment at community pharmacies in New South Wales, Australia. International Journal of Drug Policy 2008 19:450–458

 

Launch of Suboxone Film - Sydney Olympic Site - August 2011

 http://methadone-research.blogspot.com.au/2011/09/launch-of-suboxone-film-sydney-olympic.html

 

Suboxone Sydney launch 2006

 http://methadone-research.blogspot.com.au/2006/04/suboxone-sydney-launch_9505.php4

 

Lenzer J. Why we can’t trust clinical guidelines. BMJ 2013;346: f3830

 http://www.bmj.com/content/346/bmj.f3830

 

 

 

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

QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Pani PP et al. Cochrane Database CD008939

 

Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Kao D et al. Ann Intern Med 2013

 

Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Wedam EF, Haigney MC. Addiction 2013

 

False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H et al. J Pain Res 2013 [full citations below]

 

 

 

Dear Reader,

 

Before commenting on these four recent items, here is my summary of the state of play: “While distressing and serious, torsade de pointes tachycardia is a very rare event in methadone patients.  This arrhythmia is highly treatable with a low or zero mortality rate judging from the cases reported in the literature since 2002 (n~100).  Torsade de pointes appears to affect the older patient population (>40 years), is more common in women and generally when higher doses of methadone (>120mg daily) are combined with other drugs such as certain antibiotics and anti-virals.” 

 

These four recent items related to cardiac complications in patients prescribed methadone.  While the Cochrane review finds insufficient evidence to advise any interventions on this subject, the other three papers are disappointingly thin on facts and high on the ‘fog’ factor despite the clarity now appearing after a decade of clinical experience since Krantz’s seminal report of 17 cases in 2002.  [Cochrane abstract: http://www.ncbi.nlm.nih.gov/pubmed/23787716?dopt=Abstract ]

 

Kao, Krantz (senior and corresponding author) and colleagues purport to present an ‘analysis’ of FDA adverse event reports.  Their torsade figures include reports which were not primarily due to methadone (43% not primary suspect) and further, it also comprises reports of QT prolongation without a break-down of these two very different syndromes.  Hence to arrive at the actual number of torsade reports where methadone was the primary suspect one needs to discount 361 by 43% and then take account of the proportion of torsade cases (figure not given here but was about 70% in Pearson’s paper).  This makes about 2 reports of torsade tachycardia per month in America.  About half would have been dependency cases (FDA information).  See my own more detailed description and conclusions [ http://methadone-research.blogspot.com.au/2013/07/can-adverse-event-reports-inform.html ].  [Abstract can be accessed here: http://www.ncbi.nlm.nih.gov/pubmed/23689766?dopt=Abstract ]

 

 

In an ‘Addiction’ editorial Wedam and Haigney write discomforting and confusing words about the so-called “QT prolongation phenomenon”.  Why call it a ‘phenomenon’ any more than a fever in an infant with an infection?  But it serves to spice up the ‘mystery’ which scientific discourse is meant to dispel.  Many commentators and public health authorities have called for more substantial research on this subject, preferably national surveys.  Yet now that such research it to hand from Norway and France (sudden deaths in Norway and torsade reports in France, all very reassuring and consistent) many writers seem to ignore its outcomes.  Wedam and Haigney cite the Norway article by Anchersen but then states that Americans must be different to Europeans!!  Their citations do not (and cannot) justify such a position, making the contention no more than a ruse to confuse. 

 

This ‘Addiction’ editorial continues a long history of apparent antagonism to methadone treatment.  Their titles would seem to support this while few of the items would appear to be productive issues aimed at improving patient care or public health goals.  Topics included cravings from additional methadone, memory problems, injecting of methadone, benzodiazepine abuse, deaths, and more. [full Addiction article available on line: http://onlinelibrary.wiley.com/doi/10.1111/add.12123/full ]

 

 

The third item is a chronic pain case report of such an extraordinary nature that it can have little or no relevance to regular clinical practice.  Veteran author Dr Cruciani (senior and corresponding author) and colleagues surprisingly publish a detailed day-to-day report of a complex pain patient who was clinically overdosed with methadone given parenterally along with pethidine and other opioids.  The most telling features relative to cardiac safety would include: the lowest QTc values (317, 416ms) were found on the days after the highest methadone doses (334, 363mg).  One slightly prolonged reading (451ms) occurred two days after methadone was ceased altogether.  These findings are consistent with the literature in which normal QTc levels were commonly found in patients who had torsade de pointes away from the tachycardia episode (and also large diurnal variations in QTc values).  A single ECG tracing is almost certainly a waste of time for routine purposes in low or perhaps even high-risk patients.  And despite all the prolonged QT levels this patient still did NOT develop any arrhythmia. 

 

 

While torsade de pointes is extremely uncommon, it will still be seen occasionally in dependency and pain practice.  The arrhythmia needs to be considered in someone with fainting, fitting, palpitations, shortness of breath or occasionally, chest pain.  Treatment involves the use of urgent paramedic treatment and transfer to cardiac intensive care for monitoring.  Some patients will need intravenous magnesium, temporary pacemaker and/or cardioversion.  Withdrawal or replacement of the suspected drugs and/or reduction in doses may be useful.  There is no single agreed protocol for this condition but its treatment should be directed by cardiac experts, just as dependency should be directed by dependency experts and pain by pain management experts. It is crucial not to avoid appropriate doses of methadone as the risk of inadequate doses is very substantial, including death, whereas there he never been a reported confirmed death due to torsade de pointes.

 

As Pani et al. point out there is no proven preventive strategy but it would seem prudent to order a cardiograph on patients who are prescribed high dose methadone (>150mg), especially if there are any other risk factors.   

 

Comments by Andrew Byrne ..

 

Full citations for these articles:

 

Pani PP, Trogu E, Maremmani I, Pacini M. QTc interval screening for cardiac risk in methadone treatment of opioid dependence. Cochrane Database Syst Rev. 2013 Jun 20;6:CD008939

 

Kao D, Bucher Bartelson B, Khatri V, Dart R, Mehler PS, Katz D, Krantz MJ. Trends in reporting methadone-associated cardiac arrhythmia, 1997-2011: an analysis of registry data. Ann Intern Med. 2013 21;158(10):735-40

 

Wedam EF, Haigney MC. Opioid addiction agonist therapy and the QT prolongation phenomenon: state of the science and evolving research questions. Addiction 2013 108;6:1015-1017

 

False sense of safety by daily QTc interval monitoring during methadone IVPCA titration in a patient with chronic pain. Miranda-Grajales H, Hao J, Cruciani RA. J Pain Res 2013 6:375-8