April 5 2006
Product launch by Reckitt Benckiser. Suboxone combination drugs containing buprenorphine and naloxone 8mg/2mg and 2mg/0.5mg approved in Australia from April 1 2006.
Dear Colleagues,
This was an auspicious evening put on by the plush Rydges Jamison Hotel at Wynyard in central Sydney. After elegant canap�s of Beijing duck, sushi and bonsai pies with tomato sauce, Eric Strain from Johns Hopkins Medical Center gave a comprehensive description of the development of the combination drug. He showed numerous slides of his own pharmacokinetic and pharmacodynamic studies. He started by asserting that adding naloxone to opioids was an effective and time-honoured practice. Apart from the New Zealand experience (which resulted in the combination drug's eventual withdrawal), he quoted previous 'successful' uses with pentazocine (Fortral/Talwin), methadone (patented in the 1970s) and tilidine (Valeron) as having stemmed abuse. We were given neither criteria nor references for this conclusion.
Dr Strain emphasised that the withdrawal reaction to injected buprenorphine and naloxone in those already dependent on other opioids is 'very unpleasant' but GENERALLY (my emphasis) not harmful. He did not cite the reports of serious adverse events, including sudden death from injected naloxone in the literature (Osterwalder 1996; Andree 1980). We were also told of a trial (corroborated by some data on blood levels) showing that subjective effects of three types of buprenorphine were maximal in the liquid preparation, medium in the pure sublingual product and least in the combination tablet at a given dose level (the first differences were significant but the second trend did not reach statistical significance). We were then told by Dr Strain, supported by Chris Chapleo of Reckitts, that the formulation type had little effect on absorption. Surprisingly, Dr Strain seemed unaware of the common practice of using 'granulated' (semi-crushed) tablets in Australia. He speculated as to whether the citrus flavour of the newer preparation increased salivary flow, facilitating absorption (it might just do the opposite - but studies are limited). Some blood level studies showed higher levels in the combination product, others lower or the same. I was surprised that none of the speakers covered the only published clinical trial comparing the new product with other modalities (Fudala 2003).
Next we had a choice of grilled salmon tranches on mash or ox cheek braised in red wine with turnip, baby carrot resting on artichoke or chestnut puree and jus. Joining the 'coalition of the willing', Dr Mike McDonough then gave an eclectic account of his unit's contribution to a multi-centre study of 130 patients treated with unsupervised combination buprenorphine. He described having to deal with many unexpected occurrences, each involving a new learning curve in randomised subjects taking weekly non-supervised (dispensed) treatment. We heard of scenarios where patients who were originally assessed as being 'stable' subsequently revealing worrying and unpredicted problems. One had taken a mixed drug overdose needing emergency resuscitation. Another patient reported that cutting their own dose by half, leaving sufficient tablets for a trip to Perth but with some unpleasantness on return to Melbourne. So even in very experienced hands stability is hard to gauge.
Dr McDonough then quoted Robinson's paper from Wellington, NZ from 1993 [their finding was that after pure buprenorphine was banned and almost entirely replaced with the combination product due to abuse, 63% of new dependency patients were still using the drug, most by injection. Subjects also stated that it was 'easier to obtain' and that the black market price was lower a year after the change to combination product. And the drug was subsequently withdrawn completely]. We were also reminded of James Bell's study but were reassured that the finding of 50% dose increases reported on changing from pure to combination product was probably due to "anxiety" (no references) and that the doses 'returned back to previous levels after a while' (which is not my reading of the paper - they did decrease, but not back to original levels on pure buprenorphine). We all await publication of further data on the fundamental issue of dose equivalence.
Ms Susan McGuckin, the representative from NUAA (a NSW consumer advocacy group) spoke eloquently about the frustrations of being a consumer is such a volatile field. She also supported more choices for doctors and patients.
Next we had the arrival of Professor Bob Batey, breathlessly brandishing hot-off-the-press copies of a 'draft' set of NSW guidelines on buprenorphine/naloxone prescription for addiction. He reminded us of the inevitable diversion which can be expected and the fact that it is not just take-away policy which drives such markets. His words were more of basic clinical common sense than revealing any brave new frontiers. It was the first time in my experience that a new health department policy was announced at a drug company event.
We were told that questions would only be taken at the end from written submissions on cards supplied to each of the dozen or more round tables. They were to be addressed to a panel in the final session during coffee by the chairperson.
Following bread and butter pudding with summer berries and clotted cream, question time was not very encouraging as Dr Strain was asked to predict events if the combination drug is injected. He gave likely outcomes in the various scenarios, apologising for the length of his reply. He seemed to have difficulty responding to a more specific query about whether a current buprenorphine patient would get a withdrawal reaction if they injected the combination product. Others have stated that such patients can inject buprenorphine 'with impunity' and a withdrawal reaction is highly unlikely (one called it a "best kept secret"). Dr Strain, on the other hand stated that it was a difficult matter to predict but that on balance, he thought that the situation would probably be 'dose related' and that under 8mg would probably cause euphoria while higher doses would be likely to cause withdrawals. These uncertainties may reflect the limited research in the area, making it all the more difficult for regular clinicians to make decisions.
One public sector member of the audience asked if the combination product was being pushed for reasons of patent or 'evergreening' to secure market share. Dr (PhD) Chris Chapleo of Reckitts told the audience that his company had no patent over either product, although he said later that there were 'exclusive licence' agreements in some countries 'in return for the company's input into research and development' but that these did not apply in Australia or New Zealand.
A further question was read out by chair Dr Alison Ritter as to whether the combination product could be chemically converted into its constituents by enterprising amateur chemists. Chris Chapleo stated that short of having a complicated chemistry equipment and knowledge this was most unlikely, and his company had tested several proposed amateur methods, finding that they did not work (one tried to oxidation of the naloxone with potassium permanganate). My own reading of the manufacturer's prescribing instructions indicates that the two drugs have quite different solubility properties. Hence by adjusting temperature, granulation and simple dissolution and filtration, an enterprising kitchen 'cooker' might find this quite simple, as many do with mixed analgesics currently. Dr Charles R (Bob) Schuster, who is doing post marketing surveillance of buprenorphine in America, wrote recently in Drug and Alcohol Dependence: "It is unlikely, however, that any formulation can be developed that cannot be altered by 'street chemists' into a more abusable form."
A final card was read out, questioning if we were all "missing something". Were we all 'ignoring the elephant in the room?' This was put to the silent audience but after such generous hospitality (although not a drop of alcohol) it may have seemed unfair on our hosts to ask the clinical questions:
- Can we be sure of dose equivalence between pure and combination product?
- Are there clinical studies to show that the combination product is safe and effective? Fudala's 28 day comparative study - the only one of its kind - was not dealt with by any of the speakers on the night, but it did have some data for up to 11 months.
- Why is there no 0.4mg tablet for the new product? Thus at a common dose level of 4mg daily the only possible reduction is 50%. For methadone (or insulin, or warfarin) this would be considered inappropriate or at best a 'courageous' reduction.
- Why are the new products not 'scored' like the pure ones which are easy to break in half? As stated in the NSW guidelines on combination buprenorphine presented on the night, it is acceptable for patients to take half doses morning and night to avoid sedation or other side effects.
- There appear to be TWO quite different concepts arising out of the new product: (a) combination buprenorphine may have a lower abuse potential and (b) a totally new claim that unsupervised use is safe and effective for addiction treatment. While we would all hope both of these will be true, to date, neither has been subject of more than one or two limited preliminary studies. Hence claims for their appropriateness would seem premature, especially considering pure buprenorphine and pure methadone have stood the test of time when given in traditional medical settings.
- Can injecting naloxone be dangerous? In what ways? Can we be held responsible if the drugs we prescribe are used contrary to our instructions? Can we reduce the harms?
- Should women of child bearing age be prescribed this drug combination, given the lack of safety data for naloxone in pregnancy?
- Since it is agreed that partial antagonists like buprenorphine and pentazocine already cause precipitated withdrawals when used (injected or otherwise) by subjects who are currently using other opioids such as heroin or methadone, one may ask what is the point of adding naloxone? We also do not know if the new product is safer for injecting than the existing pure product with regard to 'chalk', 'filler' or other non-active constituents?
- And we should not forget: this treatment is generally less effective and less cost-effective that methadone. Combination buprenorphine does not have long-term safety data like methadone. If methadone is considered better for pregnant women, why not also for others?
James Bell had the last word of the evening, saying that the combination product is not a 'third drug' as another participant had stated. It is still the buprenorphine we are all used to, only now being used under a different 'paradigm'. He said that taking the focus away from supervised treatment and back towards other more important clinical matters would be a great challenge to everyone in the room. [He had told another meeting recently that unsupervised treatment may be shown by experience to be completely unworkable and we might have to be withdrawn entirely ... 'only time will tell'. It seems odd to me to take such risks in peace time.]
We should all be grateful to Dr Strain and his colleagues for their pioneering studies on the combination drug, although from the questions, this audience was still anxious for more direct clinical information on the new drug and its possibilities.
Reckitt Benckiser is to be congratulated for taking the risk on this new formulation in an attempt to improved dependency treatments in Australia. We could not expect this launch to be an update on all opiate treatments, a subject which is being left to the College of Physicians with a new series of regular workshops generously sponsored by Reckitts.
Comments by Andrew Byrne ..
Refernces:
Osterwalder JJ. Naloxone for intoxications with intravenous heroin and heroin mixtures - harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol. (1996) 34;4:409-416
Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784
Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958
