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

Canadian injecting centre success. Addiction journal article

Addiction 2007 102;6:916-9

Wood E, Tyndall MW, Zhang R, Montaner JSG, Kerr T. Rate of detoxification service use and its impact among a cohort of supervised injecting facility users.

Dear Colleagues,

Finally we have some direct evidence of the benefits of injecting facilities in reducing drug use and encouraging treatment. This is in addition to their primary goal of protecting their clients while still using injected drugs. This paper counters the claim that such harm reduction measures �entrench drug use�. In fact, those who attended the Canadian injecting room were MORE likely to have attended detoxification and other forms of treatment in the year after the facility opened. The increased uptake of detox services was statistically significant. While the clients were mostly still active street drug users, their use of the injecting services diminished while treatment entry increased.

This paper should silence the few remaining honest critics of injecting services. They not only save lives, they also encourage a referral pathway into treatment services and they do not encourage more drug use. While many of us had a gut feeling this was the case, it is reassuring to find it supported in this high quality peer reviewed article from Canada.

Comments by Andrew Byrne ..

Abstract herewith for those interested in more details.

Background

Vancouver, Canada recently opened a medically supervised injecting facility (SIF) where injection drug users (IDU) can inject pre-obtained illicit drugs. Critics suggest that the facility does not help IDU to reduce their drug use.

Methods

We conducted retrospective and prospective database linkages with residential detoxification facilities and used generalized estimating equation (GEE) methods to examine the rate of detoxification service use among SIF participants in the year before versus the year after the SIF opened. In secondary analyses, we used Cox regression to examine if having been enrolled in detoxification was associated with enrolling in methadone or other forms of addiction treatment. We also evaluated the impact of detoxification use on the frequency of SIF use.

Results

Among 1031 IDU, there was a statistically significant increase in the uptake of detoxification services the year after the SIF opened. [odds ratio: 1.32 (95% CI, 1.11-1.58); P = 0.002]. In turn, detoxification was associated independently with elevated rates of methadone initiation [relative hazard = 1.56 (95% CI, 1.04-2.34); P = 0.031] and elevated initiation of other addiction treatment [relative hazard = 3.73 (95% CI, 2.57-5.39); P < 0.001]. Use of the SIF declined when the rate of SIF use in the month before enrolment into detoxification was compared to the rate of SIF use in the month after discharge (24 visits versus 19 visits; P = 0.002).

Conclusions

The SIF's opening was associated independently with a 30% increase in detoxification service use, and this behaviour was associated with increased rates of long-term addiction treatment initiation and reduced injecting at the SIF.

Three recent journal items: alleged problems with cannabis, methadone and buprenorphine

Dear Readers,

I try to give credit when it is due. However, at the same time there should be a �gong� for less-than-inspiring articles which make it thru the peer-review process. There are a number of contenders for my wooden spoon award � which I hesitate to write about, lest my words raise their prominence unduly. But in the interest of fairness, I present here a number of publications which would have been returned for rewriting had I been the editor.

Paradoxically, some of the findings, while inadequately clad, are potentially of clinical importance.

�Gong� award number 1:

Pollack HA, Reuter P. The implications of recent findings on the link between cannabis and psychosis. Addiction 2007 102:173-176

This lead editorial lurches from confidence in the American system of drug control to admissions of wholesale failure of the same. There are no �recent findings�, hence there are no useful �implications�. No mention of the Dutch situation or medicinal cannabis. �Don�t mention the war!� (on drugs).

�Gong� award number 2:

Gossop M. Methadone - is it enough? Heroin Addict Relat Clin Probl 2006;8(4):53-64

This is written as if methadone were some carrion being encircled by birds of prey. Despite being an excellent alternative, buprenorphine does not rate a mention in this long, tedious article. After reiterating the proven benefits of methadone, Gossop states: �Supporters of methadone maintenance bring discredit upon themselves and their treatment [sic] by mean-spirited attacks on other forms of treatment.� (no references). My review of this edition includes another fraught article by Krantz on the supposed cardiac risks of QT prolongation in methadone patients (copy on request).

My final �gong� goes to a research item of certain interest but with conclusions which are completely at odds with its data:

Kakko J, Gr�nbladh L, Svanborg KD, von Wachenfeldt J, R�ck C, Rawlings B, Nilsson L-H, Heilig M. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. Am J Psychiatry 2007 164;5:797-803

This Swedish report claims to support buprenorphine as the first line drug for addiction despite a 65% failure rate (dropout or transfer). Indeed, the findings showed that those randomised to buprenorphine fared poorly, even though final retention rates in the two groups were the same. Most needed to transfer to methadone to achieve such an outcome. Read the full summary for all the other problems (such as early bup drop-outs; mean bup dose of 29mg; drug company sponsorship).

We are all learning (me especially), and as a prominent author wrote to me, all research is done in its own context. While pure science is always welcome, real-world practice requires that there be a combination of information to advise clinical decisions. The above articles yield very little new in this regard.

Comments by Andrew Byrne ..

Addiction journal Feb 2007 lead editorial: questionable logic.

Addiction 2007 102:173-176

Pollack HA, Reuter P. The implications of recent findings on the link between cannabis and psychosis.

Just when we thought the last word was in on this issue, the Addiction journal has its lead editorial as a poorly written, confused 'hypothetical' on cannabis and psychosis. It seriously concludes (with no evidence quoted) that cannabis might just turn out to be much more harmful than was 'thought' (they don't say by whom), needing new policies to restrict its use. Rather than being a balanced review of this interesting if less than earth-shattering issue, we find two respected authors speculating a worst-case scenario should research prove cannabis to be much more harmful than previously believed. They contradict themselves by reiterating at least three times that law enforcement has little impact on consumption, yet at the same time, assuming a 20% drop can be obtained using certain (unspecified) punitive measures.

Despite being in a European journal, here we have a uniquely American or 'drug war' perspective given equal footing alongside scientific or evidence-based approaches with which these authors are obviously familiar but unwilling to address in parallel with their current subject.

Despite the wild speculation about possible unexpected dangers, the authors completely ignore the fact that doctors prescribed this drug for much of the 20th century with few adverse consequences reported. They also completely ignore the Dutch experience where cannabis has been available for adults to purchase for many years with low community rates of cannabis use (especially in the young) and few adverse events. Equally, they ignore the lack of any reported increased prevalence of psychosis in areas of very high cannabis use.

Their alarmist speculation might make some sense if this were a newly introduced drug, but it has been used for generations and is unlikely to show up completely unexpected adverse effects on which these authors speculate. Indeed no cannabis deaths have ever been reported while most other drugs, even seemingly innocuous ones, have a reported mortality (penicillin, aspirin, MDMA).

Despite mentioning the relative harms, known and unknown, of cannabis, the authors at no point try to put these harms into context of other drugs such as alcohol, tobacco, ecstasy, cocaine, etc. If they had, readers may realise that quite contrary to their stated logic, the more dangerous a drug is, the more cogent the argument that it be controlled or even supplied by the state. Under this system, substantial reductions have been made in consumption of alcohol and tobacco in many western countries.

Perhaps predictably, these authors ignore the possible benefits from cannabis. Just as alcohol probably has some benefits for certain groups, so, along with possible prescription use, cannabis availability might result in net benefits to certain users and even society generally. One feasible means might be through reductions in the use of other more dangerous drugs such as alcohol and tranquillizers.

I read on, expectantly waiting for some new reports of a link between cannabis and psychosis but there was none such. They vacillate from calling the drug 'marijuana' to the correct medical term, cannabis, as in their title.

These authors bemoan a lack of longitudinal research including cannabis, yet they fail to cite Fergusson's landmark reports on the subject which are both detailed and comprehensive.

Fergusson has reported a probable association and a possible causative link between cannabis use and a small proportion of psychosis cases. He feels that the jury is still out, but that the numbers are not large. Neither he nor these authors express any great faith in legal constraints in reducing cannabis use. Despite this, the Addiction authors bring up a ludicrous hypothetical of cost-benefit relation between a 20% reduction in cannabis use and savings to society by a purported 1.6% reduction in schizophrenia cases. They freely admit the difficulties of measuring consequences of criminal convictions such as family breakdown, work and education disruption, not to mention the occasional cases of long-term residents being deported to unfamiliar third world countries as a 'double punishment' which is not unheard of nowadays. Adding to their delusion, these authors try to persuade the reader that while most countries would be unlikely to agree to increase penalties for cannabis use or possession, they propose that the USA is the most likely country to do so!!

It is hard to understand the rationale behind this editorial. Does Addiction peer review (or even proof read) their editorials?

The rest of this edition has an array of interesting and relevant articles if one is not put off by the first three pages of drivel.

Comments by Andrew Byrne ..

EUROPAD journal December 2006: poor articles, poor editing, best ignored

EUROPAD journal December 2006

Heroin Addiction and Related Clinical Problems. December 2006. Editor Icro Maremmani, University of Pisa.

This journal�s advisory panel boasts a bevy of senior members of the addiction specialty world-wide. Yet the quality of its articles in the December edition is well below the standard we find in other dependency journals. The quality of some items is almost embarrassing in that they lack basic aims, a coherent structure and execution.

The �diatribe� of Gossop (Methadone - is it enough?) is most disappointing, coming from someone so eminent and experienced (see below for my personal vivisection). His subject could be interesting, but he develops the sentiments as if methadone was to be seen in total isolation rather than as just one tool in the dependency repertoire, also forgetting that methadone is one of the commonest pathways towards long-term abstinence. He does not even mention buprenorphine once in the entire long article! It would be like saying �Penicillin is not perfect!� Well, of course it isn�t!

Editor Maremmani�s opening editorial is confusing and poorly argued. He writes about �Discarding the Label "Substitution Treatment" in Favour of "Behaviour-Normalization Treatment". He states (incorrectly): "We remember that Dr. Dole never spoke about �substitution treatment� and that, in his experience, methadone was a behaviour-normalizing drug which would re-balance the endogenous opioid system persistently damaged by toxic narcotics such as heroin. This happens only when methadone is administered at adequate dosages and as a maintenance regimen."

This is putting words in the master�s mouth on several counts. I knew Vincent Dole quite well. Maremmani also misquotes Vincent Dole on the terms 'replacement' or 'substitution' treatment. I recall that Vince Dole did not particularly care what MMT was called, as long as it was given in sufficient doses with appropriate supports and safeguards. It would seem that Maremmani himself does not read his own journal since Dr Dole himself is quoted in this very issue (p13) "From this perspective methadone maintenance is replacement treatment, compensating for impairment in function of natural opiate-like substances" [Dole VP. Methadone maintenance: Optimizing dosage by estimating plasma level. J Addict Dis 1994 12: 1-4]. Maremmani also published an article entitled: �Opioid Substitution with Methadone ��. Also, contrary to his statement above, heroin is not necessarily a �toxic narcotic�, just as methadone is not always a 'behaviour normalizing' drug. The opposite can also be true since heroin may be therapeutic while methadone may be abused.

So why would Icro Maremmani write such confusing, unreferenced material? Like Gossop in the same issue, he writes about methadone as if buprenorphine, long acting morphine, prescribed heroin and dihydrocodeine did not exist! Do they have a serious "agenda" or could they just possibly be operating on auto-pilot, I wonder?

Editor Maremmani certainly works quickly. He �received and accepted� 4 of the five articles on the same day that they were received. Only one item (Reisinger on injection of buprenorphine) took him 2 months to decide on. Perhaps he ought to have spent more time editing and less time �opinionating�. The item by Schmittner and Krantz on cardiac effects in methadone patients is also flawed and unbalanced in my view.

Reisinger grapples valiantly with the difficult subject of buprenorphine injecting. As there is almost no controlled research on the subject, his findings and conclusions are as valid as any.

�QTc Prolongation in Methadone Maintenance: Fact and Fiction.� Schmittner J, Krantz MJ.

This opens with a statement that methadone was: �until recently, was viewed as a medication without cardiac properties.� Krantz should know this to be untrue since he has previously cited a study from the 1970s (Lipski) which had a major incidental finding that a high proportion of (unstable) methadone patients had QT changes. It is hard to know why this subject is even being discussed at this level when there is still not one series in the world literature of symptomatic, documented cases from the large ranks of �normal� MMT subjects. In fact, I have still not read of one single convincing case, although it is quite certain that �torsade de pointes� must occur at some rate in 'normally' treated dependency patients just as it can occur in those on other medication or indeed in those not taking any drugs, due to a familial predisposition.

In recent articles and talks, Krantz and colleagues have been saying that (1) we need to be really careful about providing �high� (>120mg) doses of methadone (2) there is a therapeutic 'paradox' that higher and (therefore) �more dangerous� doses of methadone are also proven to be associated with lower rates of illicit drug use and (3) alternatives such as detoxification or transfer to buprenorphine should be considered in place of higher doses in certain (unspecified) cases. This latter suggestion is more than revealing.

In my view these three pieces of advice are unhelpful and inappropriate. They could even be dangerous. Do these authors believe that clinicians were not 'careful' before this issue was raised by them? As with other medication, doctors should only prescribe when non-drug treatments have proven ineffective and then, we should always employ the lowest effective dose of the most appropriate drug. If we followed Krantz' (unspecified but guarded) advice, our patients may actually stand to develop MORE torsade de pointes through increased illicit drug use. His original report involved a high proportion of pain management cases and the mean dose was 397mg daily, while 15 out of 17 (none of whom died) had other risk factors for QT effects and tachycardia. If any of the drug abuse patients were using cocaine then the appropriate response may be higher doses of methadone which are proven to be protective in this regard (see Borg, Kreek et al).

The present article tells us blandly that: �The likely mechanism of arrhythmia development is blockade of the human cardiac ether-a-go-go-related gene (HERG) delayed-rectifier potassium current.� Who are we to argue, yet this is not very helpful for a �side effect� which is still not established, and if it were is certainly extremely uncommon. Certain dangerous situations such as overdose, needle sharing and 'dirty injections' are every day occurrences in our patient group and these can be reduced dramatically by simply optimising doses of methadone (in England the average was reported by Strang to be 37mg daily!! No wonder they think MMT does not 'work'!).

Krantz has also stated again that his revelations will be of even more importance with the 'worldwide expansion' and community use of methadone treatment in the future. What does he mean? That we need to slow down the opening of methadone clinics in China or South America because of his important work? He has yet to publish an estimated prevalence of torsades in regular MMT subjects treated under existing guidelines (it would be difficult, since there appear to be no series of such cases). From reports to FDA cited by Peles and Kreek the prevalence of such complications may be one in ten million doses. This makes aspirin look mighty dangerous!

Krantz has stopped writing about 'torsades' (which may or may not occur as a result of 'normal' dependency treatment) and now just addresses �QT prolongation� (which does occur as a result of methadone doses, but is usually asymptomatic). �Prolongation� is mentioned 28 times in the article, �torsade� only twice (excluding references). In his original article of 2002 �torsade� was mentioned 27 times while prolongation only thrice. The point is that QT prolongation is usually asymptomatic condition while torsades is an arrhythmia which is quite often fatal. It seems that most of the small number of cases are from tertiary referral centres in patients with complex medical illness as well as high doses of methadone in combination with other drugs, legal and illegal.

Gossop M. Methadone - is it enough? Heroin Addiction and Related Clinical Problems. December 2006.

This article is one of the least edifying pieces of medical writing I have read. It is still a mystery to me why so many intelligent colleagues in England keep going around saying the same old things, viz: that methadone maintenance treatment (MMT) is not perfect and so there must be a better way, or words to that effect. Strang wrote that methadone may yet have a �sting in the tail�. Well of course MMT is not perfect, and that is why we need alternatives, such as the new heroin injecting trial in England (not mentioned in this article for unknown reasons; nor is the fact that it has taken British colleagues 27 years since Hartnoll's last published work on the subject).

Appropriate medical treatment of addiction involves some patients taking methadone for certain periods. Gossop knows that. We know that. It also involves some patients taking maintenance buprenorphine, others having short detox episodes, others still longer term rehabs, etc, etc. Gossop�s tedious discussion over reduction versus maintenance 'programmes' is awkward, unproductive and academic. Despite some doubtless well-meaning intentions, such distinctions are almost always blurred and ill-defined, thus making them irrelevant clinically.

So it is a mystery why anyone would waste breath, time and effort discussing shortcomings of the very modality which has been so well researched for 40 years. Especially so when many of these shortcomings refer to the English experience reported in NTORS (National Treatment Outcomes Research Study). This latter �study� is almost meaningless scientifically, yet it parallels good research done by John Strang and colleagues that the quality of MMT in England is so poor that mean doses have been reportedly as low as 37mg daily.

Apart from poor editing [eg. "In some respects, it is encouraging that only a minority of patients showed achieved such poor outcomes." p59], he studiously avoids discussion of the important and even crucial issue of dose supervision. And they also bring up the �canard� that there is "still controversy" over dose levels! Dose guidelines in almost every country now agree (most patients need 60-120mg daily with a small proportion needing more or less for metabolic reasons). Despite many differences of opinion of details of treatment, dose levels is one area in which there is very little controversy left amongst addiction experts. One might equally say vaccinations and insulin treatments are 'controversial' which they very well may be in minority quarters.

Almost every doctor who has every prescribed methadone for any length of time has had certain patients taking over 100mg and who are demonstrably doing well and who fared less well on lower doses. Vincent Dole's first report of 25 patients had several taking 180mg daily and an AVERGE dose of 106mg daily. So why would Gossop regurgitate irrelevant and confusing information? While it is true that most controlled research has involved patients taking lower doses than 120mg, it is also true that most patients in US clinics where most such research was performed were taking less than 120mg, hence the circular argument on research relating to doses. In fact there is now quite a substantial literature demonstrating that higher doses benefit a proportion of people who otherwise on these apparent recommendations here would count as failures. Hence it is inescapable that from what is written here, if taken seriously by our newer colleagues in Eastern Europe who are targeted by this Journal, could cause sub-optimal treatment to be given. If they looked at the article in an even slightly less positive light, they may well decide not to prescribe methadone at all. It is hard to imagine any other area of medical practice in which we would see 75% response rate to a single drug in a �negative� light, as Gossop appears to. For rheumatoid arthritis, diabetes, depression, hypertension, etc, this response rate would be impressive indeed.

How could one possibly write a serious article about the limitations of methadone without even mentioning buprenorphine? My guesstimate is that the introduction of buprenorphine into normal dependency practice over 7 years has improved outcomes in my own practice from about 75% (much the same as Gossop�s quoted figures) to over 90% on normal outcome measures. We may learn more from up-coming Scandinavian controlled research on the subject.

Few of these articles would have been accepted by serious medical journals in my view.

I recommend avoiding this journal in favour of the mainstream literature. Readers may be surprised at me recommending Addiction, published by the Society for the Study of Addiction in England. To receive this journal at �mates rates� one need only join the society for 75 English pounds. This includes 12 Addiction issues plus supplements and Addiction Biology plus an internet subscription and access to a web based notice board and chat line (which sadly is hardly used by anyone, it seems).

Comments by Andrew Byrne ..

Buprenorphine trial patients mostly end up needing methadone: Swedish RCT

Am J 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 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. The final mean dose of buprenorphine was 29mg daily (�5). Consistent with previous research, only a third of buprenorphine patients remained on the treatment (42% transferred to methadone while 21% dropped out, most notably in the first 3 weeks). Treatment was 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 attendance with the remaining doses given as �take-away� or dispensed doses.

The authors claim that retention rates in the two groups were �virtually identical� 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, one in eight appear to have departed the trial. Methadone had about the same number of people leaving treatment overall (22% in six months), but they did so at a more constant rate over the 6 months of the trial. Overall 80% of methadone patients remained in treatment at 6 months, a commendable result, probably partly due to the good treatment given and lack of alternatives in this community.

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

Despite these predictable findings, the authors initially state 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 50%, especially when there was an acceptable, cheaper and more effective alternative. The methadone in this very trial showed a failure rate of 20%. In addition, methadone is considered the drug of choice in pregnancy.

The only reason given for using the combination buprenorphine/naloxone drug was that 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 for 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 as 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 their case is not helped by a majority of their patients needing methadone in the long run and mean doses of buprenorphine being so much higher than other reports.

We are informed that the 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� (is that English?) from buprenorphine/naloxone to methadone. Yet such patients must have been doing poorly on buprenorphine and must have had some views on finally being prescribed a 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.

It would also be interesting to know how many of the methadone patients may have needed to transfer to buprenorphine (we find it is between 10 and 30% in our own practice). This may well have applied to some of the drop-outs and possibly some of those retained in the treatment, who may be preferred to have buprenorphine for a variety of reasons.

Comments by Andrew Byrne ..