21 April 2014

"Is the War on Drugs Over?" New York panel discussion.

April 4, Vanderbilt Hall, Law School, NYU. "Is the War on Drugs Over?" A Panel Discussion on the Drug War's Effects on Human Rights and US Policies.
 
Three panel members (the fourth cancelled in unfortunate but almost humorous circumstances) were very actively chaired by Mattathias Schwartz. 
 
Kathleen Frydl is an award-winning historian of US policies.  Her most recent book, Drug Wars in America 1940-1973, was hailed by SUNY Professor Paul Gootenberg as "the most compelling scholarly book to date written on … America's post-war transition to punitive domestic drug policy". 
 
Hamilton Morris is a research chemist and an expert on synthetic and psychedelic drug and contributes to Harper's and is science editor at Vice, where he hosts "Hamilton's Pharmacopeia", a video series. 
 
Cesar Gaviraia served as President of Colombia from 1990 to 1994 and Secretary General of the Organisation of American States from 1994 to 2004.  He is a member of the Global Commission on Drug Policy, which has advocated a shift towards de-criminalization, harm reduction, and demandside anti-drug programs. 
 
Michael Botticelli is Acting Director of the White House Office of National Drug Control Policy, also know as the office of the drug czar.  He previously served as Director of the Bureau of Substance Abuse Services for the State of Massachusetts. [cancelled and no substitute available]
 
Vice drug ‘czar’ Mr Michael Botticelli was missing in action having apparently had an underling call the moderator earlier to cancel.  We were told an amusing description of the chain of events.  Moderator Mr Swartz asked if another drug office person might fill in and when that was declined, even the staffer, who seemed to be very knowledgeable about the subject himself, was asked if he would like to attend and represent the Government.  No go.  
 
This chain of events is hardly surprising in the current climate where popular opinion and science are diametrically opposed to long-time official Washington policy.  One of the pertinent comments of the evening was a question as to how one might get members of a prohibitionist orientated administration “into the same room” as the activists, doctors and public health experts.  My answer from Australian experience would be to wait until a member of one of the high profile families is affected by drugs or, even more likely, affected adversely by current drugs policy in America. 
 
The moderator was highly effective young journalist Mattathias Schwartz who writes on national security and state power for The New Yorker, the London Review of Books, and other publications.  "A Mission Gone Wrong," his most recent New Yorker story, gives a history of the drug war as waged abroad.  [A rather long-winded but fascinating article available on http://www.newyorker.com/reporting/2014/01/06/140106fa_fact_schwartz?currentPage=all  ]
 
This meeting was one of the most enlightening I have been to in some time.  It was held in the beautiful and high-tech Vanderbilt lecture hall at NYU Law School near Washington Square.  Three eminent speakers and an ‘on-side’ (the side of reason) moderator were unanimous in agreeing that the drug war was not yet over, although signs were present that an end might be in sight, at least for some aspects of that long, expensive and unproductive conflict/noble experiment. 
 
Mr Schwartz asked ex-President Gavaria if he would still condone his government’s pursuit and assassination of Pablo Escobar in 1993.  Schwartz repeated his proposition that Escobar might have just been replaced by another king-pin anyway and asked if it was therefore right to go ahead with his killing.  Gavaria had no hesitation is saying that as a fugitive and acting against the country’s rule of law that ‘of course action had to be taken against him’.  However, the ex-President followed up by saying that the breaking of the Escobar cartel made little if any difference to the flow of drugs northwards which continues to this day unabated.  Mr Gavaria emphasised that only measures which affect demand in the consumer countries can have any meaningful effect on this. 
 
El ex-Presidente then spoke at length about numerous issues, belabouring and berating journalists and politicians especially for their lack of attention to drug related matters.  He described modern journalism as the ‘art of the unusual’, (making quite a lot of sense to my mind).  He said that nobody wanted to hear about public health statistics but anecdotes, even those contrary to trends, are more likely to be published prominently than small changes elsewhere which might save hundreds of lives.  He gave an example of legalisation of cannabis in which a teenager has a car accident and kills a family while intoxicated even though the ‘main game’ of crime, corruption and medical consequences are far more significant to the country. 
 
He then told us that one of the worst consequences of being placed on ‘schedule one’ meant effectively that scientific research on that drug was effectively prevented as the drugs could only be obtained in exceptional circumstances with enormous paperwork and safeguards.  Hamilton mentioned that this was a ‘disaster’, especially for LSD and numerous other drugs which had shown promise in certain diverse medical and clinical fields, migraine being just one he mentioned.
 
Morris Hamilton then mentioned that just one day before the seminar, naloxone had been approved by the FDA for public dispensing.  An off-label nasal formulation of the opioid reversal agent has been widely circulated already in some states.  ‘Evzio’ will be marketed by Kaleo but it is not clear who will pay  the estimated $200 for each unit - which will include audible instructions once the unit is opened, rather like a defibrillator.  http://www.bostonglobe.com/lifestyle/health-wellness/2014/04/03/fda-approves-user-friendly-device-reverse-opioid-drug-overdoses/aPUzTAmmY0uMGQn3PwMR7H/story.html
 
In addition, we were given some intriguing information about the leglisation of all synthetic cannabinoids in New Zealand, contrary to trends elsewhere to continue banning anything which appeared to be popular (see http://www.huffingtonpost.com/2013/08/02/new-zealand-drug-law_n_3696809.html  )
 
Other panellists pointed out the fallacy of banning a relatively safe drug like cannabis when legal alternatives may turn out to be far more dangerous and are only or largely used because of prohibition of the progenitor.  ‘Spice’, ‘bath salts’ and other designer drugs were mentioned. 
 
More than once the Presidente made a statement which was highly controversial with the other panellists and some audience members: “All drugs are bad”.  He defended this, but after much goading, finally admitted that it was just necessary politically to make such statements.  Yet others pointed out that all drugs could be bad and all drugs could be good and it was the ‘set and setting’ which made the difference.  It was Paracelsus who wrote (in Latin) that the difference between a poison and a drug was just the dose.  That might apply to homeopathy as well. 
 
Ms Frydl made the point that she was ‘agnostic’ about good and bad with drugs.  When it comes to what should be more strongly regulated she said that such decisions should be based on evidence of actual harms, and the consequences of regulation.  So often it was said that the bans were more harmful than the drug itself.  She mentioned work of the DPA and the legalization issues and an audience member pointed out that DPA supremo Ethan Nadelmann was present in the room.  He had in fact just been in New Zealand giving a keynote address to a conference partly devoted to the new synthetic drug laws. 
 
It was pointed out that prohibition did sometimes work as with methaqualone and some analgesics.  Yet the flat balloon analogy was used by El Presidente that if you restrict one popular drug then another will take its place very quickly, sometimes with disastrous consequences.  One panel member said that recent changes in availability of prescribed opioids in places like Vermont had cause them to be largely replaced with street heroin which in turn had been associated with very high numbers of overdoses … every one preventable.  Vermont has one single methadone program which is totally inadequate for a state which has a rural population and long distances for most residents to reach such a facility.  Fortunately buprenorphine is available for some who can afford it. 
 
In question time I made a comment about the lamentable reluctance of Americans to allow their doctors to prescribe methadone and of their pharmacists to supervise its administration.  Ms Frydl interjected that methadone is always available in clinics in this country (a rather pusillanimous sentiment considering waiting lists and high costs to consumers).  I was surprised but touched that the Colombian ex-President said that some of the most sensible comments and arguments he had heard had come from Australian physicians (probably including Dr Alex Wodak who often speaks common sense at international forums on the subject). 
 
We were told that one major factor in the repeal of alcohol prohibition in America was the fear of the general population that they would be subjected to income tax, something which only affected the very rich in that era.  Legalising alcohol again would ensure a flow of excise funds to government to use for schools, hospitals, etc.  I had never heard of this before, always assuming that it was the ‘mothers of America’ who were campaigning against the occurrence of truancy and drunken school children who were the main force against the prohibition of the 1920s.  Maybe it was both. 
 
Very brief and incomplete summary of this informative talkfest - written by Andrew Byrne ..

9 April 2014

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.
 

2 December 2013

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."

 
 

2 August 2013

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
 
Suboxone Sydney launch 2006
 
Lenzer J. Why we can’t trust clinical guidelines. BMJ 2013;346: f3830