Email/Medline exercises examining use of combination buprenorphine naloxone in clinical practice.
Dear Colleagues,
The combination buprenorphine product is due for release in Australia in April, as 2mg and 8mg buprenorphine with 0.5mg and 2mg naloxone. Australian states and territories have been using the pure product (0.4mg, 2mg and 8mg sublingual tablets) for almost 6 years and it now accounts for between 10 and 50% of the opioid maintenance 'markets'.
There have been claims that the combination is clinically equi-potent and that it is subject to significantly less abuse. While sublingual naloxone is only partially absorbed (~10%) it may still have side effects in the longer term. It might also be the reason why some patients request a higher dose when taking the combination product (see Bell et al 2004 in which a mean increase of about 50% was required). While research on (pure) buprenorphine is extensive and consistent for addiction, work on the naloxone combination is scanty and conflicting. We need to consider that some of the prescribed combination drug will be injected (in Wellington, NZ, more than 50% of addicts presenting for treatment in 1992 were reportedly doing so). This will predictably cause toxic reactions in some users for which we need to be cognisant.
For these reasons we performed a literature search of naloxone using Medline and find that it is not always benign when used intravenously. Below we list some citations which seem relevant (note that none relates directly to maintenance treatments). We also sent an email request to American colleagues on their experience after nearly 4 years of clinical use of the drug using office based (non-supervised) prescription in that country. This is a summary of the findings.
Methods:
An email request was sent to 184 US colleagues (see wording below). The recipients were drug and alcohol workers who had indicated an interest in the field and who received regular journal summaries sent by email from our surgery. Some details of respondents and responses are tabulated here, along with some selected quotes. The recipients included substantial numbers of university professors, clinicians, drug users, advocates, policy makers and researchers, many of whom responded.
Results:
There were 44 responses received, 5 being from 'secondary' recipients making crude response rate of 24% in the busy weeks between Thanksgiving and Christmas, 2005. Of those who felt that they could comment on the issue, 16 responses came from New York, 5 from Massachusetts, 3 from California, 3 from Maryland, and one each for Connecticut, Illinois, Maine, Minnesota, New Jersey, Vermont and Puerto Rico (omits those unable to comment).
Twenty five of the 44 (57%) reported that they were personally aware of at least one case of diversion and 9 of these (20%) cited the existence of a black market with 5 (11%) quoting a street price. There was one report of primary buprenorphine addiction. A further 10 (23%) stated that they had not seen any diversion in their own practices. Two respondents no longer worked in the field. Another 7 could not answer the question from their own experience.
Analysis:
Most replies were brief but some were quite detailed. Some of the most definitive replies came from Puerto Rico and the North East of the USA. The most worrying replies came from two experienced respondents who stated that virtually all of their detox and/or maintenance patients (in three different states) had tried buprenorphine on the street in the weeks before admission. [See below for sample replies].
Conclusion and discussion:
It appears that despite reportedly low uptake of buprenorphine in America generally, in some regions doctors are prescribing the drug to the extent that a secondary 'grey' market is being reported (Cicero, 2005). Some of the street drugs reported may be 'Temgesic' obtained from Canada, Mexico, the internet or elsewhere. However, the majority would appear to be the local 2mg and 8mg combination tablets from the reports detailing the type of drug diverted. While pure buprenorphine is now available in many countries, the combination drug is currently only used widely in the US. It is also used in medical trials elsewhere (eg. Australia and ?Finland ?New Zealand - see Bell 2004).
The use of buprenorphine and buprenorphine-naloxone combination tablets in an office setting without dose supervision was introduced into the United States in unique and difficult circumstances (see Jaffe 2003) and in spite of very little published research on the intervention (Fudala 2003). Events subsequent to marketing do not appear to have been well monitored/reported as I have yet to find any meaningful data relating to the extent, safety and effectiveness of the intervention in America. There are indications of diversion (Cicero, NEJM, 2005) but these appear to be in isolated areas.
The email survey we have performed has serious limitations, being restricted to a sample of correspondents who have self-identified as being interested in dependency medicine. A true random sample of American prescribers would give more rigorous results. We believe that such a study should be performed as a matter of urgency to ascertain if indeed buprenorphine or buprenorphine-naloxone products are being diverted to a street market at a rate which is of concern.
In my view, until more is known, non-supervised opiate maintenance treatment should generally be used in the context of increasing access to take-away doses ['take-homes' or 'carries' in US parlance] in a structured, 'stepped' or 'streamed' treatment setting. This should be based on traditional indicators of stability and progress in treatment. Another use would be in research trials comparing office based treatment with existing clinic treatment. Extended unsupervised periods (more than ~3 days) have been shown to be satisfactory for 6, 13 and up to 27 doses at a time in highly selected long-term patients after stabilisation in a clinic setting (Senay; Schwartz; Novick; Rhoades).
Appended: [1] wording of email request, [2] selections of responses, [3] references.
[1] Quoted request in buprenorphine diversion survey.
Subject: 'Use and abuse of buprenorphine (Subutex/Suboxone) query'.
Dear Colleague,
Can you let me know if you have any knowledge of the mis-use or 'diversion' of these drugs in the American community since their widespread use began about 4 years ago. They appear to be very safe and well tolerated yet we have little information to date.
Best regards for the holiday season.
Andrew Byrne .. (Sydney, Australia)
[2] Quotes
The following are selected quotes [most direct quotes, some paraphrased for clarity] of responses received:
no significant reports of misuse or diversion ... <snip> ... few serious adverse events reported
someone on the street sold him two 8mg bup/nal tablets (50 cents per mg).
I'm certainly not aware of any, but you folks might know better.
We see virtually none of it at either my clinics in [W Coast]
'remarkably little'
'expensive' [on street]
all my patients have tried bup on the street ... at $25 for 8mg ... plenty of docs give a month's supply of 32mg at the first visit and hasta luego.
regarding safety and illicit bup use in the United States. ... We are generating many anececdotal stories...
Most diversion seems to be ... from a someone for cash to abate withdrawal symptoms.
there is an illicit market for these drugs with an 8mg tab going for as much as $50.
Several .. patients .. [say] .. suboxone is available at street black market very early since its approval. ... patients have poor compliance ... almost all need supervision of medicine ... in stabilization ...
there is some diversion in NY but it is very small ... diverted buprenorphine was reported in a shelter and use by heroin addicted shelter residents
ONE of our patients in [Tri-state area] got a subutex from a "friend" and put themselves in withdrawal
there has been evidence of diversion of Buprenorphine ...mostly anecdotal.
It didn't do nothin' for me doc!
only heard of one case of street use.
'unpopular with addicts, not just due to naloxone'.
no real abuse or problems thus far.
[bup] has a bad street reputation for getting high ... [but] ... a good reputation if an addict wants to stop withdrawal.
Increasingly patients are telling me of instances where they have purchased a few pills
'little evidence of clear diversion'
one of [20 treated patients] diverted his medication, and that was to his wife
I have to get my medication from the street. The doctors here are charging ridiculous prices ... [I pay] $30 for 3 x 8mg suboxones which .. last for 2-3 weeks.
rumours .. from patient advocate group members, regarding the [New England] area. There is no question that diversion occurs...but it has not hit the papers, yet.
I've had patients report they have used bup (suboxone) provided by others
$30 for 8mg Boston
one patient ... taking extra doses of his suboxone
we ... do unscheduled "call backs" for pill counts [for] detection of diversion ... .
anecdotal reports from needle exchange customers who have used or plan to use street-acquired buprenorphine
addicted unable to get bupe elsewhere
some anecdotal reports suggesting that the little diversion ... for the purpose of trying out the treatment.
[3] References:
Cicero TJ, Inciardi JA. Potential for Abuse of Buprenorphine in Office-Based Treatment of Opioid Dependence. NEJM (2005) 353;17:1863-5
Jaffe JH, O'Keeffe C. From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States. Drug and Alcohol Dependence 2003 70 (supp) 2:
Osterwalder JJ. Naloxone -- for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409-416.
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Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784.
Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther 1967; 157: 420-426.
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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
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Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376-378.
Brimacombe J, Archdeacon J, Newell S, Martin J. Two cases of naloxone-induced pulmonary oedema -- the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19: 578-580.
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