30 May 2007

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.


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.


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.


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).


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.

29 May 2007

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 ..

16 May 2007

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 ..

9 May 2007

Methadone side effects; separating fact from fiction

Tuesday 20 March, 2007

The evening began with Dr Adam Winstock's overview of a recent study of about 1000 patients on methadone and buprenorphine, suggesting high rates of side effects: sweating, sexual dysfunction, sedation and constipation. Patients wanted help with these issues but many had not discussed them with their opioid prescriber. The biggest problem regarded as a consequence of methadone / buprenorphine was dental difficulties. Surprisingly there were few differences in side effect profiles between either medication, and other than sedation there was no clear dose relationship with any side effects, nor a relationship with the duration of treatment.

Since side effects are problematic and can be reduced with appropriate treatment in some cases, and since many patients� attributions are incorrect, managing side effects should be more frequently addressed in consultations according to Dr Winstock. Fewer side effects may lead to better retention and improved health generally in the drug dependent population.

Dr Richard Hallinan then looked at hormonal, sexual and dental problems in methadone maintenance treatment (MMT), starting with some quite early studies. In 1970, over 200 MMT patients retrospectively compared their current complaints with their time before MMT (Bloom and Butcher 1970). 80% on MMT (versus 3% before MMT) complained of weight gain; 40% (versus 15%) of increased use of alcohol; 70% (versus 58%) constipation; 32% (versus 12%) numbness of hands and feet; and 60% (versus 49%) had difficulty with ejaculation.

However, a prospective study of 180 men and women before and during MMT (Garbutt and Goldstein, 1972) showed improvements in most physical symptoms during MMT, including aches and pains in muscles, bones and joints, craving, sweating, anorexia and nausea, headaches and insomnia, with little change in constipation, impotence and climax problems.

What are addicts like before MMT? Wilczek et al (2002) reported test results on over 100 men and women before they started MMT, finding low haemoglobin (24%), elevated CRP (25%), low testosterone levels (in males, 63%). Imaging methods revealed hepatomegaly in 28% and splenomegaly in 27% with liver steatosis in 15%.

Does methadone cause obesity? Szpanowska-Wohn et al (2004) reported statistically significant growth of body weight, in 48 men and women during 9 months of MMT, with fewer underweight and more overweight or obese people. Given the prevalence of overweight and obesity in the general community, it is however not clear whether this is a return to "societal norms" or a direct causal effect.

Do people on MMT have sexual dysfunction? Compared with 41 normal controls, Teusch et al 1995 found 37 MMT men and women differed significantly in sexual interest, emotional arousal, physiological arousal, performance and orgasm satisfaction. However as noted above, they may be better or little different from their time on heroin.

A number of studies have shown that plasma testosterone is lower in male heroin addicts than controls. Many studies in animals and humans have shown that opioids suppress testosterone, acting at the level of the hypothalamus to reduce secretion of gonadotrophins: "hypogonadotrophic hypogonadism". Amenorrhoea is common in women using heroin, and menstrual cycles tend to normalise during MMT (Schmittner et al 2005).

However, studies of men on prescribed opioids have given contradictory results. Only 10% of 92 MMT men reported by Brown et al (2005) had low testosterone, but low mean testosterone was reported in 54 men taking oral sustained-action opioids for chronic pain (Daniell, 2002); and also in 37 men on methadone maintenance (Bliesener et al 1995) while the mean testosterone level of buprenorphine-treated patients did not differ from that of healthy controls. Bliesener et al suggest buprenorphine might be preferred over methadone for this reason. Daniell has called for androgen replacement for men taking opioids who have low testosterone, citing low energy, muscle weakness, sexual dysfunction and higher risk of osteoporosis.

Wilczek and Stepan (2003) reported on bone mineral density (BMD) and metabolism before and during MMT, finding that heroin addicts had low average BMD; after one year of MMT, BMD remained unchanged, although osteo-resorption and -formation markers normalised. Recently Kim et al 2006 have reported osteoporosis in 35% and osteopenia in 48% of 92 patients in MMT, with male gender, lower weight and heavy alcohol as risk factors. However this study group may have been at higher risk (eg high rates of HIV medication and the possibility of self-selection in the study recruitment).

On the available evidence, screening for osteoporosis probably should be targeted, rather than universal, in men and women on MMT: heavy alcohol smoking, poor diet, history of low stress fractures, and hypogonadism are risk factors to consider.

Two studies have reported reduced sperm quality in men on MMT and in heroin addicts: Cicero et al in 1975, but in these studies controls were lacking or poorly matched and alcohol may have been a confounder.

Several studies have shown high caries rate and severe periodontal disease in heroin addicts, and excessive intake of food with a high sugar content is common (Scheutz 1995, Zador et al 1996). Although drug addicts often only realized how poor their dental health had become during periods of abstinence (Scheutz, 1995), caries increments were higher among people on methadone maintenance than current heroin abusers, but not statistically significant (Scheutz, 1984).

Opioids, like antidepressants, anti-cholinergics and HIV medications, may cause xerostomia (dry mouth) and this is considered a risk factor for dental disease (see Concord Seminar 20 May 2003. Dental problems in addiction treatment subjects: does methadone rot teeth? Can we prevent dental decay? Dr Peter Foltyn).

Gingivitis is a reversible inflammatory disease of the periodontal tissues, and periodontitis, in addition, involves destruction of the supporting structures of teeth. Smokers are more susceptible to periodontal diseases, and alcoholics compared with 100 non-addicts exhibited intensive dental caries (Gerlach and Wolters 1977). Poor periodontal health with reduced salivary flow has also been reported in people with chronic HCV, and use of cannabinoids has been associated with increased xerostomia (dry mouth) and severe gingivitis (Fazzi et al 1999).

Despite all of these potential confounders to a relationship between opioids (prescribed or illicit) and dental and peridontal disease, a detailed epidemiological study with control for confounders is still lacking. In the meantime, it is reasonable to give the following oral health advice to people on opioid replacement treatment:

"Give up smoking. Brush your gums, not just the teeth. Make sure your diet is balanced and avoid excessive high sugar foods. If dry mouth is a problem, try oral lubricants (like 'Oral Balance') especially at night, and dry mouth toothpaste and mouthwash (eg 'Biotene' toothpaste + mouthwash). Avoid alcohol-based mouthwashes, which dry the mouth."

Dr Andrew Byrne then spoke on constipation, sweating and prolonged QT in methadone maintenance.

Constipation and sweating are common in patients on methadone, probably more commonly at high doses but also at quite low doses such as 30mg daily. The symptoms are usually of a minor nature and require no more than sympathy, explanation and reassurance. Occasionally these may be severe enough to need further attention. If they are ignored, some patients may even drop out of treatment.

Constipation can mean different things to different people so clarification is needed about frequency, consistency, bleeding, haemorrhoids, bloating, diet, etc. There is no single approach but we should always address exercise, fluids, diet and consider laxatives or suppositories/enemas if other measures fail. Specialists advise avoiding bowel irritants such as senna and related compounds since these can cause colitis in long-term use. Luminal agents such as Magnesium sulphate, mannitol, lactulose, etc can be used while there are combination products which some patients find acceptable (Movacol, Microlax, Coloxyl with danthron).

Sweating likewise can occasionally be so troublesome that patients need help. There may be saturated clothing in the daytime while at night, sheets and pyjamas may need changing due to excessive sweating from methadone. The precise cause is unknown: candidates include hypothalamic and autonomic mechanisms, and histamine release. There may be multiple aetiologies since some get it after the dose, others when in withdrawal and other still at unpredictable times. It may also be seasonal and can respond to reassurance and slight dose reductions.

Two medications may be worth trying. The drug loratadine (�Claratyne�) is an over-the-counter �non-drowsy� antihistamine. A stronger and more specific medication is the anticholinergic drug propantheline (�Pro-banthine�). The latter may cause dry mouth, dizziness and other autonomic side effects so patients may wish to cut it in two (which needs a pill cutter as the tablet is not scored).

Dr Byrne then pointed out that purported methadone related cardiac conduction problems were like a Miss Marple mystery without a body. After 40 years of successful use across the world it would be unlikely that a serious side effect would suddenly be recognised. And, despite the initial report in 2002 by Krantz and colleagues of 17 non-fatal cases on high doses (average 400mg daily), there has still been no series of cases reported in regular maintenance patients.

Prolonged QT and ventricular fibrillation remain rare complications of many common medications, often also involving serious concurrent metabolic and structural disturbances. Krantz, who has written about the possible dangers of prolonged QT interval in Lancet, does not recommend ECG in new MMT patients. The NSW Health Department has advised performing a cardiac assessment including electrocardiogram for patients who are being considered for high dose methadone (>200mg daily). This would seem to be a reasonable precaution.

In the second half, several case "vignettes" were presented, including three cases of low testosterone in opioid-treated men.

Gert, 41 yo, on MMT with a current dose 70 mg, was found on screening to have low total testosterone: 5.5 nmol/L; his testosterone dropped to 3.7 nmol/L despite methadone dose reductions to 55mg. Luteinising hormone (LH) was low. His BMI was 29. Abdominal ultrasound showed fatty liver. His dual energy X-ray densitometry (DEXA) scan showed osteoporosis, with lumbar T-score -2.6.

He was seen by an endocrinologist, and on questioning admitted to low energy, low libido, increasing erectile dysfunction, hot flushes, weight gain in last 12 months. Prostate examination and specific antigen (PSA) were normal. He was started on androgen replacement with "Androderm" patches, with resolution of his hot flushes, low energy, low libido, and erectile dysfunction. However patches caused skin irritation, and he much preferred "Sustanon" injections, and later testosterone transdermal gel. At follow up DEXA a year later, lumbar T-score had improved to -1.9.

This brief presentation was filled in after questions from the audience: Gert's testicular volumes were normal. Liver function tests, full blood count, thyroid function tests and prolactin were normal. Visual fields were normal (cerebral CT was not done). The main reason for treatment in this case was osteoporosis (not sexual dysfunction, which the patient had not actually complained about). Testosterone assays were performed in the morning, as recommended.

We were reminded of the Australian Endocrine Society for androgen replacement treatment: for persistent hypogonadism (at least two morning testosterone levels below 8.0 nmol/L); if there are symptoms of low energy, mood, muscle strength, sexual dysfunction, especially if there is osteopenia, osteoporosis. Prefer testosterone and its esters to synthetic androgens, check the prostate and PSA in men >40yo. Beware the marked placebo effect that often occurs with androgen replacement, which may lead to subsequent disappointment.

It was pointed out that haemochromatosis should have been considered in the differential diagnosis (the endocrinologist in this case notes that haemochromatosis and pituitary tumour are the 2 classic exclusions for the diagnosis of hypogonadotrophic hypogonadism. In this case no other clinical features of haemochromatosis were present, but hypogonadism caused by iron deposits in the pituitary can present in isolation from other features of haemochromatosis. Iron studies were normal in this patient).

The second case was Ben, a 31 year old labourer from regional NSW, who had been on buprenorphine maintenance the last 2 years, after previous MMT. His alcohol use was very heavy from his late teens, he injected amphetamines from age 21 and heroin from age 23. He was HIV, HBV and HCV seronegative and liver function tests were normal.

With his buprenorphine dose 8-12mg daily, he was prescribed sildenafil as he had formed a new relationship and complained of erectile problems. His total testosterone was low at 7.3 nmol/L with low LH, and he was referred to sexual health physician. Penile Doppler was normal, and there was a poor erectile response to a prostaglandin challenge. Follow up testosterone was 8.7 nmol/L. He was advised that his erectile dysfunction was psychogenic.

Ben continued to have erectile dysfunction, and resented needing PDE-5 inhibitors. He reduced his buprenorphine dose precipitously, then returned needing dose supplements. Continuing reductions were accompanied by a rise in testosterone in to the high normal range, but erectile dysfunction remained intermittently a problem.

A year later his wife blamed buprenorphine for their failure to conceive, insisting he come off treatment, despite by now normal testosterone. Ben was was worried about his sperm count. After counseling, they attended a fertility clinic. Ben's sperm count was normal, his wife's ovarian cyst was removed, and �they� become pregnant 8 weeks later.

After reducing his dose to 0.4 mg, Ben came off buprenorphine with protracted symptoms requiring mirtazepine, clonidine, and eventually temazepam. He was off BMT for the birth of his son, but relapsed into heroin use 8 months later.

This case illustrated the risk that sexual dysfunction may destabilise opioid replacement treatment; that buprenorphine can be associated with low testosterone and sexual dysfunction; that androgen replacement is not necessarily needed whenever testosterone is low.

Bill was a 56 yo man, on MMT continuously since 1991, his current dose 65mg. He had injected heroin since age 22. His current alcohol use was 70-140g/day, and he smoked 10 cigarettes/day. He had chronic back pain after a minor injury in 1999, and fractured his right humerus after slipping in a puddle 2002. He was admitted to hospital with (?aspiration) pneumonia in 2000.

Bill had Dupuytrens contractures, spiders, palmar erythema. His blood tests showed elevated GGT and AST, normal ALT, low platelets (130), normal haemoglobin but macrocytosis. He was HCV seropositive and repeatedly HCV-RNA negative.

His morning total testosterone was 10.0 nmol/L and 7.2 nmol/L on two occasions (normal 12-36). With his worsening kyphosis, X rays showed wedge fractures of the thoracic spine, and loss of height in lumbar spine. DEXA showed osteoporosis (T score -4.1 spine and -3.0 at hip). Serum folate was low at 3.7 (>7.0).

Bill was referred to an endocrinologist, who noted his low BMI (18.8). Coeliac screen, and 25-OH Vitamin D were normal. A repeat total testosterone was 12.1 nmol/L.

After dental review, bisphosphonate was prescribed, with calcium supplements and folate.

Among the �messages� of this case: the likely importance of alcohol, smoking and dietary factors in the genesis of osteoporosis in this man; the need to check other causes of macrocytosis in an alcoholic; and again, the need not to rush in with androgen replacement.

Finally there was a case vignette, to put things in perspective: "I've been on a hundred mils of methadone a day for 25 years and I'm as fit as a fiddle! Most of the people who I started using with are long since dead. I consider methadone has kept me alive, and is the best tonic ever invented."

Summary written by A. Winstock, R. Hallinan and A Byrne.

6 May 2007

Research on buprenorphine and naltrexone now 30 years old.

Dear Colleagues,

The latest Swedish and American reports (Kakko 2007; Brigham 2007) mark 30 years since the first papers on buprenorphine for addiction treatment. With naltrexone also just 30 years old, it is instructive to draw a birthday parallel between these two opioid derivatives which have such very different characteristics. Each was proposed for addicion treatment in the 1970s when methadone was just becoming established as a useful modality for certain addicts at certain times in their lives (Resnick 1977; Jasinski 1978). Early work with buprenorphine showed favourable results while naltrexone trials had limited results involving poor compliance and high relapse rates (Tucker 2000). Randomised placebo controlled trials of naltrexone for relapse prevention showed no effect (San 1991, Lerner 1992).

The research on buprenorphine has become ever more focused on improvements to the original successful work. Several RCT’s, second daily dosing, higher doses, flexible dose, combination with naloxone, blood level measurement, community use with less supervision and other innovations have been tried and tested. These outcomes have taught us more about its successful use in clinical practice and the treatment of drug addiction has been improved dramatically as a result.

On the other hand, good research with naltrexone is quite limited. Both relapse prevention and rapid detoxification seemed to be associated with overdoses, suicides and other negative consequences (see Miotto 1997). Rather than giving up, staunch naltrexone enthusiasts continue to this day trying it in new and customised methods, mostly with small numbers and using protocols so varied that fair comparison is not possible (see Camarasa 2007 n=10). With poor results from oral naltrexone, some proponents have taken to using ‘home-made’ and largely untested implants. They are bound and compounded in a variety of ways which are meant to cause slow release from under the skin incision made for their insertion under anaesthetic. The largest implant currently is reportedly being used by the Chinese and is 7 grams (= 7000mg).

This constitutes an uncontrolled community trial and reports are conflicting and hard to interpret. Some units report “no deaths” publicly while acknowledging in meetings that dozens have occurred in patients who have been treated with naltrexone, but saying that ‘naltrexone did not cause any deaths’ (sic). The first reports of detoxification under sedation (using bromides) were reported in the British Medical Journal over 100 years ago (and deaths were reported then as well).

We should continue trying to match appropriately assessed patients with optimal treatment. It would seem that for many patients a brief history will reveal what works for that individual and what does not. For new patients needing opioid maintenance we should still consider methadone the drug of choice. Kakko reported an 80% success rate against half that for buprenorphine. Oral naltrexone should probably not be used for relapse prevention due to a lack of evidence. Implants are still experimental. Many regular addiction workers have met addicts who have dropped out after naltrexone implant treatment. Most of the 50 or so that I have met state that they would not have had the treatment if they had known all the facts at the time. Many have paid very large sums of their own money for these unapproved treatments (not FDA, TGA, PBS or manufacturer approved as rapid detox or implants). The first RCT on naltrexone implants will be eagerly awaited by the field. The same scrutiny and safeguard are necessary for naltrexone as for any other drug doctors prescribe.

Comments by Andrew Byrne .. (references below) http://www.redfernclinic.com/


Kakko J, Grönbladh L, et al. A Stepped Care Strategy Using Buprenorphine and Methadone Versus Conventional Methadone Maintenance in Heroin Dependence: A Randomized Controlled Trial. American Journal of Psychiatry 2007 164;5:797-803

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

Camarasa X, Khazaal Y, Besson J, Zullino DF. Naltrexone-Assisted Rapid Methadone Discontinuation: A Pilot Study. European Addiction Research 2007 13:20-24

Resnick R, Kastenbaum R, Washton A et al. Naloxone precipitated withdrawal: a method for rapid induction onto naltrexone. Clin Pharmacol Ther 1977; 21:409-3.

Jasinski DR, Pevnick JS, Griffith JD. Human pharmacology and abuse potential of the analgesic buprenorphine. Archives of General Psychiatry 1978 35:501-16

Tucker TK, Ritter AJ. Naltrexone in the treatment of heroin dependence: a literature review. Drug Alcohol Rev (2000) 19;73-82

Lerner A, Sigal M, Bacalu A, Shiff R, Burganski I, Gelkopf M. A naltrexone double blind placebo controlled study in Israel. Israel J Psychiatr Rel Sci 1992 86:983-990

San L, Pomarol G, Peri JM, Olle JM, Cami J. Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts. Br J Addict. 1991 8:983-90

Miotto K, McCann MJ, Rawson RA, Frosch D, Ling W. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug and Alcohol Dependence (1997) 45:131-134

MacLeod, N. Cure of morphine, chloral, and cocaine habits by sodium bromide. BMJ (1899) 15/4/1899 p896-898

5 May 2007

Redfern Hep C article published. Treatment feasible and effective.

Dear Colleagues,

Our article on hepatitis C is published this week.

We describe a population of injecting drug users taking methadone and buprenorphine treatment (n=237) with a HCV seroprevalence of 75%. A third of seropositive people had risk factors for disease progression and were targeted for referral for possible treatment. There were 27 who attended a liver clinic during the 3 year study period, of whom 14 started treatment with pegylated interferon-alpha and ribavirin, most with very gratifying results. [At latest count 24 patients have been treated]

Hallinan R, Byrne A, Agho K, Dore GJ. Referral for chronic hepatitis C treatment from a drug dependency treatment setting, D&A Dependence 2007 88;1:49-53

abstract: http://dx.doi.org/10.1016/j.drugalcdep.2006.09.018