Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated hepatitis C virus-specific harm reduction

Drug and Alcohol Review 2007 26;4:437-43

Hallinan R, Byrne A, Dore GJ. Harm reduction, hepatitis C and opioid pharmacotherapy: an opportunity for integrated hepatitis C virus-specific harm reduction.

The Byrne Surgery. Redfern, NSW, Australia.

While harm reduction advocates, policy makers and practitioners have a right to be proud of the impact of interventions such as needle and syringe programmes on HIV risk, we can be less sanguine about the ongoing high levels of HCV transmission among injecting drug users (IDUs) and the expanding burden of hepatitis C virus (HCV)-related liver disease. In this Harm Reduction Digest Drs Byrne and Hallinan from the Redfern Clinic and Dr Dore from the National Centre in HIV Epidemiology and Clinical Research offer a model of integrated HCV prevention and treatment services within the setting of opioid pharmacotherapy.

In their experience, this common-sense approach provides an opportunity to reduce the burden of HCV and improve overall patient management. They believe that the key elements of a HCV-specific harm reduction model include: regular HCV testing; clinical assessment and determination of need for HCV treatment referral; use of broader HCV treatment inclusion criteria; and flexibility in opioid pharmacotherapy dosing. In an environment when our macro harm reduction interventions seem to have, at best, modest impact on HCV transmission, good clinical practice may be our most effective strategy against the HCV epidemic.

This paper provides some practical suggestions as to how this can be done.

Simon Lenton Editor, Harm Reduction Digest.

The Interpretation of Urine Toxicology in Dependency Treatment. Principals and Pitfalls

22 May 2007

Speaker: Dr John Lewis, Toxicology Unit, Pacific Laboratory Medicine Services

Dear Colleagues,

Dr Lewis is one of the world�s leading experts in drug testing. His speaking manner combines what T. S. Eliot might have termed a lugubrious drollery with a profound grasp on his subject. It is easy to be light-hearted about �piss tests� but it is also deadly serious if your own job, drivers licence or liberty depend upon such a result.

We were reminded first up what urine testing can NEVER determine with any accuracy: (1) the dose, (2) the time it was taken or (3) the pharmacological effect of any substance being tested.

The most common drug assays they perform are for methadone and metabolites, cannabinoids, opiates, cocaine, benzodiazepines and amphetamines. Barbiturates often omitted these days since their illicit use seems to have ceased for all practical purposes. The term �amphetamine type substances� (ATS) is now superseding �sympathomimetic amines�. This group includes dexamphetamine, methylamphetamine, ecstasy (MDMA), methylenedioxyamphetamine (MDA), and other �designer� drugs such as paramethoxyamphetamine (PMA) and their metabolites, but also ephedrine, pseudoephedrine. One needs to know the particular immunoassay �kit� being used to be sure what exactly is detected and at what level.

Laboratories are asked to perform tests both in a clinical setting as well as for forensic, workplace or medico-legal reasons. For clinical purposes a cost effective and fast turn-around time approach is used. This starts with an inexpensive immunoassay which is very sensitive for most of the drugs being tested for, but generally not specific. Hence a negative batch of tests can yield a fast, efficient response to the clinician. Positive immunoassay results for any of the drug groups (or negative for methadone) may indicate further testing, typically using GCMS (gas chromatography/mass spectrometry), which is considered the �gold standard�. Although thin layer chromatography (TLC) is not commonly used nowadays, Dr Lewis says it still has a place: it presents information on a large range of drugs to view at a single glance, and is inexpensive. Because the TLC depends upon the human factor of recognising patterns, it is subjective and unless the spot patterns correspond to known medication, confirmatory testing by mass spectrometry is usually conducted. Although it is not used for medico legal work, it still has a place in clinical settings, as an adjunct to mass spectrometry in presumptively identifying a wide range of therapeutic substances not amenable to immunoassay.

In particular cases there will need to be specific tests done, especially for suspected drug use which may not be detected by the usual immunoassays. These include tests for doctors, nurses or other health care workers on conditional registration due to drug use. Such drugs include pethidine, tramadol and the short acting anaesthetic propofol. Abuse of these drugs outside the medical setting is exceptional.

Note that buprenorphine is also hard to detect by simple methods. Although there is an immunoassay for the drug, toxicologists must be aware of possible false positives from a number of unrelated therapeutic substances. However, like methadone, when the dose is taken under supervision such testing is less important than, say, in England where much treatment is unsupervised and testing for the prescribed medication can be crucial in determining compliance and overall stability.

Dr Lewis then detailed the limitations and strengths of modern immunoassays in determining a class of drug but only in two cases can they detect specific metabolites, EDDP (for methadone) and 6-mono acetyl morphine (heroin). The value of a negative test was pointed out. We were reminded that testing was almost pointless in hospital casualty cases: for overdoses, the results are usually not available until either the patient is dead or else recovered. Also, medications are used so routinely and such patients may have injuries necessitating local anaesthetics, dressings, iodine, etc in the course of their treatment in the casualty ward that results are close to meaningless.

Specifically, Dr Lewis said that positive opiate and ATS immunoassays should be taken with caution as there are many causes of false positives. These include poppy seeds, cough mixtures, decongestants and common analgesics. Dr Lewis told us that his own urine remained positive for �opiates� for nine days after a dose of the cough suppressant pholcodine. The main value of these screening tests is when the result is negative. Note that �opiate� immunoassays do not detect the �opioids� methadone, buprenorphine, pethidine and others. Oxycodone has only a very weak response to �opiate� immunoassays.

We were then shown the plates used for thin layer chromatography and a list of 20 common drugs which can be definitively determined using this method (eg. morphine, codeine, oxazepam, pseudo-ephedrine, paracetamol and nicotine). GCMS was then described in response to a question from the floor. In essence it appears that there are two properties of each substance which are identified in the method, causing a unique fingerprint from the two derived figures. It is more expensive than other methods, but more accurate and specific, being able to detect both the original base compound as well as �derivatised� products.

Then we had a brief tutorial on the use of testing for alcohol consumption. Everyone knows about breath testing, but 5% of alcohol is excreted in the urine and there is a direct correlation between plasma and urine alcohol concentration of 1.3:1. However, due to the short half life of alcohol, such testing is only of any use within hours of the drug use. And, as with other drugs, a certain level could be associated with a small amount of drug used very recently, or equally, a large amount used quite some time before.

There are also unexpected false positives, including a case Dr Lewis described where urine from a diabetic in a rehabilitation facility had undergone fermentation (probably by yeasts) before being tested; the calculated blood alcohol concentration (0.34) would have been lethal. A less �gross� error might not have been discovered, and this would have led to the automatic expulsion of the person from the rehab facility.

Tests for cannabis are of limited value since, for most, its use is not relevant to the treatment or supervision being given. Hence Dr Lewis only performs cannabis tests when specifically requested, such as in patients being treated for cannabis dependence, to assess progress.

We were then taken through some metabolic pathways. Heroin breaks down within minutes into 6-acetyl morphine, then to morphine. This then is broken down into morphine-6 or -3 glucuronide which are excreted. Codeine is largely conjugated into codeine-6 glucuronide, but importantly, a small proportion is transformed into morphine. A positive test for morphine can therefore sometimes occur due to codeine use (but not the other way around). A warning: most tests underestimate the amount of codeine in urine, as the metabolite codeine-6 glucuronide is hard to "bust" into codeine, which can be detected. It is important to know the relative amounts of morphine and codeine in a urine sample as the ratios affect correct interpretation as to what may or may not have been ingested.

Diazepam is broken down into another active metabolite, oxazepam. This can occur via two intermediaries, nordiazepam and temazepam. Most of the common sedatives and related drugs such as clobazam will show up as benzos on the initial immunoassay. However, specific confirmatory testing must be done when clobazam is used in therapeutic trials to test against �street� benzos.

Stimulants were then covered including the new definition of ice in an age of global warming (ice-bergs and all!). Amphetamine was first synthesised by the Germans in 1887. It was heavily marketed in the US in the 1930s as �Benzedrine�. Methylamphetamine is easier to manufacture, especially if one has the base product pseudoephedrine. We were then told that the latest �craze� for stimulants is purely based on stronger, highly purified drug being available in the form of �crystal meth� or �ice�. Methylamphetamine powder is a salt, "crystal" a highly purified salt, and "base" is an oil. Urine testing cannot distinguish between them as these are the same drug. While Dr Lewis� lab has found 2005 was the year with highest mean amphetamine levels, in 2006 the maximum levels found each week continued to climb to being 5 fold the 2003 levels. While these are dramatic findings, it is hard to know their significance overall except to imply that some users are taking very large amounts of methylamphetamine, viz, �ice�.

Cannabis has many metabolites which are detected on screening, and confirmed with carboxy �THC on GCMS. It is very lipophilic, and gets stored in the fat cells of the body. Cannabinoid urine tests may be negative within a few hours of a single smoke; daily use may take many days, and heavy use a month or more. If a high level is found then it is easy to know that there is continuous use. Carboxy-THC: creatinine ratios can indicate increasing or decreasing use (see case vignettes below).

Then there was a discussion about laboratory �cut-offs� which are essential for legal purposes, but less meaningful for clinical purposes, except to reduce the numbers of false positives. Cut-offs are also necessarily somewhat arbitrary, like the drink driving limits - and can vary from place to place or from time to time. Currently 50ng/ml is used for immunoassays of cannabinoids, and 15 ng/ml for the specific GCMS for carboxy-THC (plus or minus a figure for lab uncertainty; this means an actual cut off of around 18-19 ng/ml). Dr Lewis believes there is a case for higher cut-offs to be used for cannabinoids, to identify substantial cannabis use, rather than low level or more importantly residual drug from previous heavy use.

Some case vignettes in the second half illustrated common problems. Three patients with positive immunoassay for opiates claimed only to have taken codeine-based analgesics. One had codeine and morphine on GCMS, and this could be explained by metabolism of codeine to morphine, or other sources or morphine such as poppy seeds, morphine sulphate etc. Another had urine positive for morphine, and negative for codeine: this could occur if there was extensive metabolism of codeine to morphine (for example by cytochrome CYP2D6 ultrarapid metabolisers) and especially if the laboratory test underestimated the amount of codeine (see above). In the last case, urine was positive for morphine and monoacetyl-morphine: the latter can only come from heroin use.

In a case of roadside drug testing, a woman justified her positive salivary cannabis test by saying "I never smoke pot, but my partner smokes it all the time". Dr Lewis explained that this test does not pick up metabolites of THC, only the parent drug, and is not very sensitive, missing a large proportion of cannabis users (as reported by the European ROSITA study). Thus passive smoking could not cause a positive test. A man on methadone, who had not had a positive urine test for many years, blamed his positive urine cannabinoid test on his partner, who �smoked 30 cones each day�. A positive immunoassay test result is unlikely to be a result of passive inhalation. It is more likely be a false positive due to other medication, cross contamination or else laboratory error.

Dr Lewis described the benefits of using carboxy-THC:creatinine levels to help allow for variation in urine concentrations due to level of hydration. Cases were shown from the Drug Court, where declining THC:creatinine ratios were consistent with ongoing abstinence; in another case a spike in ration of THC:creatinine led to punitive action, but might have been explained by the person going to the gym, and mobilising cannabinoids stored in fat cells.

Another case from the Drug Court showed how the sequence of appearance or disappearance of diazepam metabolites (nordiazepam, oxazepam and temazepam) could be used to make inferences about recent diazepam use. In this case, as in almost every example discussed, Dr Lewis was able to give examples of exceptions, where other causes than the most obvious might account for the result. So urine tests should never be interpreted uncritically by untrained people.

In another case, a worker was suspended for producing "dilute urine" (wrongly described as a "false negative urine test") because of low creatinine urine (1.4 mmol/L), and allegedly told he would need to produce two urine tests with creatinine higher than 5 mmol/L. However, this worker's serum creatinine was low owing to lean body build, while urea, electrolytes, specific gravity, osmolality were consistent with physiological urine. THC:creatinine ratios might help adjust for hydration (some people deliberately drink lots of water to dilute their urine) but could also discriminate against people with naturally low creatinine. A urine creatinine level as low as 0.9 mmol/L is physiologically achievable. Below this suggests the likelihood, and below 0.5 mmol/L the near certainty, of external interference with the sample, usually meaning dilution after urination.

Laboratories and clinicians need to be careful with the information they give as employers may misinterpret loose terminology.

Comments by Andrew Byrne, Richard Hallinan and Judith Meldrum, from Dr Lewis� talk and power point presentation.

Buprenorphine maintenance works a treat but detox is a disaster in unselected subjects.

Time-limited buprenorphine replacement therapy for opioid dependence: 2-year follow-up outcomes in relation to programme completion and current agonist therapy status. Kornor H, Waal H, Sandvik L. Drug Alcohol Review 2007 26;2:135-142

Using buprenorphine short-term taper to facilitate early treatment engagement. Brigham GS, Amass L, Winhusen T, Harrer JM, Pelt A. Journal of Substance Abuse Treatment 2007 32;4:349-356

Dear Colleagues,

Kornor and colleagues report a 2 year follow-up of 75 patients entering supervised daily buprenorphine reduction treatment for heroin addiction. An original proposed 9 month reduction to abstinence program was extended to 10 months for compassionate reasons. Even so, only 9 (12%) had achieved and maintained abstinence at 2 years by self-report. Two were lost to follow-up and 5 (7%) died, 3 during the withdrawal phase. Half the total (37) had rejoined maintenance treatments at follow-up.

These authors imply that their research is aimed at countering restrictive policies on maintenance treatment. Norway normally only allows limited buprenorphine, in reduction courses to injectors over 24 years of age, at 3 months maximum per episode. While methadone is available for severely dependent subjects, apparently only a small proportion of the addicted population receive it. The authors conclude that continued treatment may have prevented some of the 5 deaths (3 overdoses, one suicide, one car accident). Based on the high rates of relapse following detoxification, Kornor and colleagues question the ethics of repeating this sort of reduction study in the future. Some critics (eg. Gossop) point to the limited outcomes from maintenance therapy, yet they tend to quote results of treatment given far short of accepted medical guidelines where less than optimal result are predictable.

Brigham, Amass and colleagues report on their first 64 buprenorphine “detox” patients compared retrospectively with two other groups given other treatments, including clonidine, during 2003/4. Their ‘detox’ group took a mean daily buprenorphine dose of 22mg over an average 14 days in ‘treatment’ and 80% were reported to take follow-up treatment. This compared with around 30% for the other groups given non-opioid medications.

This curious ‘study’ has limited meaning beyond indicating that giving ineffective treatment (clonidine assisted detoxification) makes patients unlikely to return for more treatment, which is hardly surprising.

These authors recognise the shortcomings of brief courses of opioids in describing “the critical need for treatment continuation following detoxification”. Their study protocol, however, rather than the stated detoxification, it was rather a ‘re-toxification’ with high doses of buprenorphine, even beyond the usual levels used for opioid maintenance. Thus by definition, their patients did not commence detoxification until after they left treatment. While reduction courses and formal detox should be available promptly to all, maintenance opioids should also be available as a ‘safety net’ where reductions fail to achieve patients’ original goal of abstinence.

The concept of arbitrary time-limited dose reductions goes against the very definition of addiction involving compulsive drug use with a certain degree of loss of control. Some will regain this control, but others will not. Despite a known higher mortality, apparently well-meaning folk continue to propose compulsory detoxification as a valid strategy. They either don’t consider that addiction exists, and/or that the consequent deaths in this group are unimportant. To do a comparable study of medication reduction using subjects with diabetes, depression or asthma would be unthinkable.

Since I have been critical of reduction courses and of using buprenorphine ‘first line’ in the past, I remain hard put to determine a rational strategy for opioid maintenance. As with other areas of therapeutics we are faced with decisions: why do we choose penicillin in place of erythromycin or aspirin against other effective analgesics? It is a combination of known efficacy of available treatments and the particular patient’s individual situation. Most often, in my experience, patients have tried methadone and/or buprenorphine so this can be some guide. The issue of pregnancy or heavy street drug use might sway one towards methadone but previous difficulties with methadone might sway one towards buprenorphine, despite its slightly lower efficacy.

So the great Dr Osler’s advice pertains: listen carefully and your patient will often tell you the diagnosis … and further, many will also tell you the treatment required.

Comments by Andrew Byrne ..

The pros and cons of pharmacy only opioid treatment from Melbourne researchers - coal face views

Drug Alc Review 2007; 26;2:143-152

Nielsen S, Dietze P, Dunlop A, Muhleisen P, Lee N, Taylor D. Buprenorphine supply by community pharmacists in Victoria, Australia: perceptions, experiences and key issues identified.

Dear Colleagues,

This large study examined pharmacists� impressions of prescribed maintenance opiates for addiction treatment in a large postal survey covering 75% of the treatment field in Victoria, Australia, relating to the treatment of about 7500 patients. It is probably the largest such survey in the world literature and had an enviable response rate with the diligence of the researchers using preliminary phone contacts and careful follow up. It may have been beneficial to have had further demographics, average dose levels, numbers of take-home doses (if any), swaps between methadone and buprenorphine, etcetera.

Both methadone and buprenorphine were available in 90% of the pharmacies involved in dependency treatment. The average had been involved for 7 years, treating a median of 16 patients each (range 1-150). Two thirds were metropolitan, one third rural or regional.

Regrettably, but consistent with other Victorian reports (eg. IDRS), the rates of reported diversion of supervised buprenorphine tablets were very high. Overall there were 33 episodes of suspected or confirmed diversion per month for every 100 patients treated. This occurred despite 82% of pharmacies crushing all doses before administration.

Sixty percent of all detected and conceded diversion episodes were stated to be for later consumption by the patient. Twenty percent said that it was to inject.

There were over 100 negative comments by pharmacists, more than half concerning diversion and administration problems. There were less than 20 positive comments from the 287 pharmacies surveyed. Most disappointingly, twelve pharmacists said that they would no longer accept buprenorphine patients due to the difficulties.

The authors speculate about reasons for the high rates of non-compliance. However, they do not question the nature and quality of the treatment being given, nor why the rates would be so different from other Australian states.

Dose levels may have been inadequate for some patients. Access to methadone, the only alternative medication, may have been limited or even discouraged. Take-away doses were very limited at the time of the study for both medications.

It is possible that some of the frustration reported by pharmacists was due to the practice of second daily (double) dosing which was strongly promoted in Victoria. Equally, universal crushing of tablets is time consuming and implies a lack of trust with patients.

Another problem with treatment in Victoria is that few if any dispensaries open early enough for labouring work hours. Hence, holding over some medication for the following day may be a temptation to diversion for those who need their dose before work.

The authors� defense of pharmacy-only treatment runs contrary to their own negative findings in this study. The authors do not make a case against a choice of alternatives such as public and private clinics, hospital, doctor�s surgery, mobile van dispensaries and jail-based treatment services. No single avenue of treatment is likely to suit all patient needs.

Hence the substantial black market reported from Victoria (and elsewhere) may well be due to a community need making a ready and willing market, possibly related to a lack of provision of accessible and appropriate services. The latter is not unique to Victoria, of course, and few jurisdictions to date have fully satisfied the need for opiate treatment services.

These authors are to be congratulated for exposing many major problems with the delivery of buprenorphine in Victoria (diversion, injecting, costs, expulsions, frustrations of health workers, etc). Further work must be done to determine why buprenorphine has apparently been so successful elsewhere as an alternative for those opiate dependent subjects who find methadone unsatisfactory.

In the meantime, it is essential that we all try to bring our own practices closer to the evidence base or �best practice�. There should be good access to a range of service delivery methods, including dedicated clinics; primary care community services for stable patients; no prejudice against methadone; no undue emphasis on 2nd daily dosing and importantly, flexible take-away dose availability (since diversion of a take-away dose is unquestionably safer that diversion of buprenorphine spat out of a patient�s mouth). Also, we should not forget adequate psychosocial supports and choice of treatment.

Comments by Andrew Byrne ..

Randomised Swedish study shows buprenorphine suits 35% versus methadone at 80%

American Journal of Psychiatry 2007 164;5:797-803

A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Kakko J, Gr�nbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M.

This prominent Swedish group may have done the field another service without realising it. A previous buprenorphine trial by Kakko et al. (Lancet 2003) had a placebo group with so many deaths (25% within a year) that they unintentionally demonstrated the life saving benefits of buprenorphine treatment (for the first time to my knowledge). They also showed that, at least in the Swedish environment with restricted access to alternative maintenance treatments, even second line treatment can yield a high retention rate of 75% at one year.

In the present study, half of 96 addicted subjects received standard methadone treatment (mean dose 111mg daily) while the rest received buprenorphine with transfer to methadone if needed. The latter occurred according to defined criteria of drug use or cravings, but only after a buprenorphine dose escalation to 32mg daily if this was tolerated. Intensive psychosocial support was also provided. Treatment was supervised daily in the first month when the trial was still double-blinded, in what these authors themselves describe as the �sensitive initial month of treatment�. After documented stability, there was graduation to twice and even once weekly supervised medication with the remainder as �take-away� or dispensed doses, consistent with good practice (see Rhoades 1998).

The final mean dose of buprenorphine was 29mg daily (�5). Consistent with previous research, only 35% of buprenorphine patients remained on the treatment (42% transferred to methadone while 21% dropped out, most notably in the first 3 weeks).

The authors claim that retention rates in the two groups were �virtually identical� (77% bup, 79% meth), yet their decay graph clearly shows an excess of buprenorphine drop outs in the first three weeks of treatment, which is consistent with the reported experience of others. There were only one or two early drop outs in the methadone group yet in those randomised to start with buprenorphine, six or more subjects appear to have departed the trial in this period. Methadone had about the same number of people leaving treatment overall but they did so at a more constant rate over the 6 months of the trial. The high retention rates are probably due to both the high quality methadone treatment offered and lack of alternative sources of maintenance treatment in Sweden.

Both groups had approximately 80% clear urine tests for opiates, also consistent with the adequacy of doses and high level of psychosocial treatment provided these subjects.

Despite these unsurprising findings, the authors write in the article�s abstract: �strategies using buprenorphine as a first line treatment should be considered�. This is changed, without additional explanation or references, to a much stronger conclusion in the text that buprenorphine �should generally be used as the first-line treatment in heroin dependence, with provisions for rapid progression to methadone when needed�. It seems bizarre to recommend a drug with a known failure rate of over 60%, especially when there was an acceptable, cheaper and more effective alternative. In addition, methadone is considered the drug of choice in pregnancy.

We are told that the combination buprenorphine/naloxone drug was chosen partly because it has been approved in the United States. From a �pure science� point of view, this clouds the issue since most research is on the pure product with very little on the combination product. The authors speculate that the addition of naloxone might have caused the high average dose of buprenorphine at 29mg daily (�5mg). The reference cited supporting dose equivalence (Johnson RE 2000) reports no such comparison from my reading of the original paper. The finding of high doses required is consistent with Bell et al 2004 (which is NOT cited by these authors, despite being the only clinical comparison to date, so far as I know). In this, patients needed approximately 50% more buprenorphine when transferred from pure buprenorphine to the combination product. They detail the low primary toxicity of buprenorphine yet they ignore some major problems reported with buprenorphine treatment (deaths in France, diversion in Victoria, injection, low efficacy, costs). They also fail to remind readers that most methadone overdose has occurred from its use outside the supervised clinic setting, meaning pain management prescriptions, break-ins, etc. See Ballesteros where only 4% of methadone overdose deaths in North Carolina in a five year period occurred in registered maintenance treatment recipients.

We are informed that this trial was partly funded by Schering-Plough Sweden. Four of the authors have received funds from drug companies. Three of these were from the manufacturer of buprenorphine and one author received funds from this source in three separate countries (Estonia, Sweden and Australia).

These authors quote the term �non-inferiority� four times in their article regarding their customised �stepped care strategy� based on retention rates and toxicology. In this comparison, however, they do not take into account several other important factors including dose, costs and patient satisfaction. They state that �no patients commented on transitioning� (sic) from buprenorphine/naloxone to methadone. Yet such patients must have been faring poorly on buprenorphine and must have had some views on finally being prescribed the more effective drug. Some might also possibly have had some views at being given the less effective drug initially in the trial, despite the consent process. Have any of these �transitioning� patients been asked to comment on the authors� suggestion relating to first line buprenorphine, I wonder? One may worry that some needle sharing or overdose might have occurred in the interim period, not to mention the 12.5% who appear to have dropped out altogether in this early period from the �stepped care� group. We are not informed if any died although in Sweden such information would probably be easily available, as in previous reports.

It would also be instructive (and equitable) to know how many of the methadone patients may have clinically indicated a transfer to buprenorphine. We find the rate is between 10 and 30% in our own practice. This may well have applied to some of the drop-outs and even to some of those retained in the treatment, who may have preferred buprenorphine for a variety of reasons. Such a matched or parallel protocol might have increased methadone retention to 90% or higher. Hence this is another flaw in the current trial and another reason to question the authors� enthusiastic endorsement of the buprenorphine combination as a first line drug in dependency treatment.

Note that an editorial by Kathleen Brady in the same issue points out several more disadvantages of the current study. Few medical practices would have the resources to give such intensive psychosocial support as occurred here. Brady uses the incorrect term �naltrexone� rather than �naloxone� no less than ten times. She also states that if injected, the �naltrexone will precipitate withdrawal�. Assuming that she is referring to naloxone, this is not the case for most buprenorphine maintained patients and only for a proportion of others with current habits on pure opiate agonists (eg. methadone, heroin or morphine). She also points out that the �stepped care� can only work if there is closely supervised treatment such as in existing methadone clinics. This would defeat the supposed purpose of office based treatment which has not been extensively tested against clinic based treatment to my knowledge. I believe that the authors are also mistaken in their choice of the term �stepped care�. This would refer to additional medication or other treatment, based on pre-existing criteria. This trial, however, uses a �safety net� or �rescue� protocol and not a �stepped care� approach in my view.

Comments by Andrew Byrne ..

References:

Ballesteros MF, Budnitz DS, Sanford CP, Gilchrist J, Agyekum GA, Butts J. Increase in Deaths Due to Methadone in North Carolina. JAMA 2003 290:40

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

Kakko J, Svanborg KD, Kreek MJ, Heilig M. 1-year retention and social function after buprenorphine-associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. (2003) Lancet 361:662-668

Nielsen S, Dietze P, Dunlop A, Muhleisen P, Lee N, Taylor D. Buprenorphine supply by community pharmacists in Victoria, Australia: perceptions, experiences and key issues identified. Drug Alc Review 2007 26;2:143-152

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