Is rapid detox followed by oral naltrexone effective?

JAMA 2005; 294:903-913

Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-Assisted vs Buprenorphine- or Clonidine-Assisted Heroin Detoxification and Naltrexone Induction - A Randomized Trial.

Dear Colleagues, The current [August 2005] JAMA home page features this item with the caption: "Anesthesia-Assisted Heroin Detoxification: Collins and colleagues randomly assigned treatment-seeking heroin-dependent patients to anaesthesia-assisted rapid detoxification with naltrexone induction, buprenorphine-assisted rapid detoxification with naltrexone induction, or clonidine-assisted opioid detoxification with delayed naltrexone induction. They found that withdrawal severity, treatment completion and retention, and proportions of opioid-positive urine specimens during 12 weeks of outpatient treatment were comparable across the 3 methods of detoxification."

In fact, there are five items in this edition mentioning naltrexone, two being letters to the editor on a long acting injectable form for alcoholism. The current feature has a commentary by Patrick O'Connor on the role of detoxification. There is also is a glowing historical tribute to Vincent P. Dole and colleagues whose seminal methadone report was published in this same summer holiday edition of JAMA 40 years ago.

With veteran researcher Herbert Kleber, this group from Columbia describe a randomised comparison of naltrexone induction in heroin addicts using three methods: (1) rapid detox under 4-6 hour anaesthetic (2) buprenorphine bolus and (3) clonidine with traditional in-patient detoxification.

The study raises several important ethical questions while also giving perhaps the last word on rapid detoxification from opioids, a century after the first report [MacLeod, N. Cure of morphine, chloral, and cocaine habits by sodium bromide. BMJ (1899) 15/4/1899 p896]. The main results are unremarkable: viz (a) that almost 100% of anaesthetised patients successfully take their first dose of naltrexone, (b) that rapid detox is hazardous, (c), that the naltrexone "treatment" is of very limited benefit (75-90% of subjects dropped out by 12 weeks) and (d) that the particular method of detoxification has no significant impact on rates of medium-term abstinence.

It is possible that some side effects in the anaesthesia group (n=35) may reflect this team's lack of experience as well as their limited ability to elicit a clear history from their patients. All three subjects who developed major anaesthetic complications are said to have had "concealed" histories (of diabetic ketoacidosis, bipolar disorder, pneumonia and sleep apnoea) from the researchers. To ascribe each anaesthetic complication to deceitful subjects is rather unusual and there may be alternative views. Others have reported lower complication rates, yet there is no doubt that such treatment can be hazardous in this population, especially if they come directly from street heroin habits.

Prescription of naltrexone for opioid addiction as a 'treatment' has only little limited scientific support in unselected candidates in community treatment. Some believe that it may have benefits in carefully selected subjects (as stated by O'Brien in the same issue p888). So why did these authors go to so much trouble to 'induct' addicts into an ineffective treatment? I note that some providers now give very frank details about the expected success rates of their treatments. Yet others have claimed '100% success' rates and call their detoxification treatments 'painless'.

It is predictable that those taking pure buprenorphine were retained for slightly longer than those given clonidine, which may be little more than a placebo in this situation. And it is self-evident that the anaesthesia patients were more likely to take their first dose of naltrexone which is given while they are still unconscious.

In his accompanying editorial Patrick O'Connor tells us that over 3 million Americans have used heroin and ten times that number prescribed opioids. Even more worrying is that over 1% of school children in the US had used heroin in 2004. Thus we are dealing with an epidemic in anyone's terms.

As with McGregor and Ali's randomised study from Adelaide (D&A Rev) rapid detox shows no significant benefits over traditional detoxification in the medium term (3, 6 or 12 months). In view of the high risks and poor results, there should probably be no further studies of rapid detoxification in unselected subjects. It is still possible that longer acting forms of naltrexone may yet prove effective for those seeking abstinence. Formal research on the safety and effectiveness of such novel delivery methods is awaited.

comments by Andrew Byrne ..

Pain management and dependency

North Sydney, Mon 22 Aug 2005

Dr Doug Gourlay

During the International Pain Conference, a meeting for 'locals' was convened by Professor Robert Batey of NSW Health at North Sydney on Monday 22 Aug 2005. We had an illuminating talk from one of the few specialists with expertise in BOTH pain management AND dependency, Dr Doug Gourlay of Mount Sinai Hospital, Toronto, Canada.
Our renowned speaker started with some definitions of addiction, physical dependency, tolerance, pseudo-addiction, with some prevalence figures in the general population.
We were given a logical approach to 'universal precautions' in opiate prescription patients. Infectious disease and dependency have some parallels: rather than isolating those already infected (eg. hepatitis, TB, leprosy) modern practice is to assume that all patients could harbour (or be victim to) infections just as all opioid recipients can sometimes demonstrate features of dependency. Thus we need to be alert and to respond with appropriate measures when needed.
Dr Gourlay reminded us of the difficulties in detecting high-risk patients on first consultation. While an accurate diagnosis is crucial to appropriate treatment, on-the-spot diagnoses are not always necessary or indeed possible in pain management and dependency. We have the benefit of seeing our patients' progress over time which allows a prospective diagnosis after accumulating more details of the patient's habits, history, examination and special tests. Predictors of progress in our field can be notoriously unreliable with some seemingly low risk patients displaying the most manipulative behaviour.
While most dependency diagnoses are made prospectively, one diagnosis we can only make retrospectively is 'pseudo-addiction'. In this, all the apparent features of addiction abate once the patient's pain has been addressed, whether physically, chemically and/or mentally. [If we postulate a 'psychic pain' and self-medication, this might be true of many dependency cases as well, since once they receive appropriate management any DSM criteria of addiction regress or even vanish.]
The items Dr Gourlay recommended we use in diagnosis included the CAGE features -Have you tried to Cut down? Do you get Annoyed by using too much medication? Do you suffer from Guilt? Have you taken medications early? 'Eye-opener' - as well as a number of other 'tell-tale' characteristics involving finances, work, drug seeking (eg. early requests for prescriptions), criminal behaviour and urine test results.
The 'tools' we have to use in dependency patients include (1) limiting quantities of medications ie. the frequency of pharmacy attendance (2) increasing doses of medications (3) utilising longer-acting forms of the appropriate medication (4) direct supervision of medication (5) supervised urine testing (6) treatment agreements � a drug diary. Dr Gourlay also reminded us not to stop opiates or benzodiazepines suddenly and that even high doses of one class of drugs will never suppress withdrawals from the other, although a transient improvement in symptoms might result. He gave a telling example of a new methadone patient denied benzodiazepines in early treatment despite a large habit. Most of our dependency patients have more than one drug habit.
Dr Gourlay has no hesitation in ordering urine tests on all his dependency patients. This includes pain management patients who have developed features of dependency - usually a small proportion, perhaps 10%. He reminded us that such testing needs to be done in a climate of trust and mutual respect. Results should never be used as a "gotcha!" manner nor used punitively. Like all pathology testing the results must only be used directly in the patient's interests. Direct observation, we were told, is not necessary in all cases but that some supervision, eg temperature testing or randomisation, is reasonable for compliance checking. We were given a compassionate and practical way to approach unexpected results. "Now I wonder if you can help me explain some unusual results we received on your recent urine specimen".
Another tool Dr Gourlay uses is a 'treatment agreement' ('never a contract') where the patient agrees to be frank about their drug use and that they will not use other sources of drugs, including prescribed medication, over-the-counter drugs or street drugs. Where they do, this should be discussed openly rather than be treated in a 'cat and mouse' manner in the therapeutic environment.
We were confronted with the statement that "no drug is addicting". Addiction requires an interaction between the drug, environment and individual. The vast majority of patients prescribed opioids never develop addiction. Dr Gourlay also said that opioids were often successful for patients with chronic non-cancer or neuropathic pain and always worth a 'trial' when other means had failed.
We were honoured to have the presence of Dr Joyce Lowinson and Dr Herman Joseph who were both associated with the early evaluation of methadone treatment at Rockefeller University in Manhattan from the 1970s.
After the main feature, we has a discussion of three complex case histories with comments from an expert panel comprising Bob Batey, James Bell, Peter Cox, John Currie, John Ditton, Paul Haber, Robert Graham and Adam Winstock. There was lively discussion over various difficulties in diagnosis and management in special circumstances, dependency, disabilities, children, alcohol, infectious disease, prejudice and other matters of mutual interest. The ethics and practicalities of urine testing was also covered.
Each case demonstrated some failings in early treatment despite warning signs being present. Each contained lessons in communications, diagnosis and a multidisciplinary, approach. There seemed some divergence of views from the panellists, but agreement with Dr Winstock that methadone is not a panacea and that psychological trauma also needs to be addressed.
For a poly-drug user on methadone for 18 years, it was surprising that with continued use of multiple opioids (pethidine and street heroin) she still was not prescribed sufficient methadone to suppress opioid use. She had also been drinking to excess and using benzodiazepines. Already taking 145mg, consideration of dose increases were not advised by all panellists. One even cautioned against consideration of blood level monitoring. It seems that some take the issue of high dose methadone in such cases to be potentially mischievous, even 'sending the wrong message' to the patient. Yet while no cure-all, we might expect that an appropriate methadone dose might reasonably be expected to suppress illicit opioid use after so long on treatment.
Dr Gourlay also stressed that in such cases, stabilising the substance dependency issues was essential before being able to deal with all the psychosocial issues that panel members had brought up ('setting boundaries'). Calling a 'case conference' is not much help if the patient cannot keep an appointment.
Dr Cox suggested admitting such complex patients to hospital as a strategy to sort matters out. Another panel member took the view that such efforts might just waste hospital resources and DG reminded us of the behavioural difficulties of such unstable cases in a general hospital setting, potentially creating resentment among staff.
Some implied a need to accept that certain situations are just not amenable to interventions. Yet in dependency practice, we often come across patients who used to be like these unhappy, unstable cases, and in whom various ministrations and time (especially the latter) have yielded stable, productive citizens in the long run.
Persistence on our part can reinforce the old saying that "when the student is ready, the teacher will appear" ... change is a process that occurs over time.

Summary of meeting by Andrew Byrne .. [final sentence and several other corrections with thanks to Dr Gourlay]

Two deaths; few other surprises; bup-combo vs clonidine for opioid detoxification.

Addiction (2005) 100: 1090-1100

A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Ling W, Amass L, Shoptaw S, et al.

Dear Readers,

This 14 day trial showed buprenorphine-naloxone prescribed patients significantly more likely to stay in treatment and stop using street drugs than those taking clonidine. It also found much better completion rates for in-patients (77%; 22%; n = 77; 36) compared with out-patients (29%; 5%; n = 157; 74) prescribed the opioid versus clonidine. Considering the buprenorphine was given in therapeutic doses of 2mg daily up to the last day, these results are not surprising.

However, it is intriguing that there are so many inconsistencies in this report from such highly respected authors. Most useful randomised trials compare an intervention of known utility with a protocol of promising but uncertain benefit - using parallel protocols and clearly defined, positive end points regarding the subjects' health. There are usually equal numbers of participants but it appears this trial was halted early by a pre-determined protocol due to the poor outcomes of the clonidine group. Unusual for 'Addiction', this multi-centre trial does not appear to have a statement concerning the funding (although the buprenorphine combination tablets were supplied by the manufacturer). Nor could I see a statement on conflict of interest. In-patients and out-patients are included but selection criteria are not given, nor are they randomised. Also unusual for Addiction, there is more than half a page of acknowledgements containing 85 names and up to 20 institutions. Several aspects of the article remind me of the sort of item contained in sponsored journal 'supplements'. One wonders if the normal peer-review process occurred, so numerous are the inconsistencies, omissions and questions concerning a lack of specific clinical aims/focus in the piece.

As above, most of the findings are predictable from the literature. The study involved a comparison of two non-evidence based 'treatments', being clonidine for detoxification and buprenorphine combination for 'detoxification'. Both 'treatments' have been shown to be ineffective in trials with over 90% failure rates on conservative criteria at medium term follow-up (1 to 3 months). Thus this study, whatever its findings, is unlikely to add to the scientific literature or knowledge base. We know that prescribing buprenorphine in standard doses to heroin addicts attracts and retains subjects while also reducing heroin use. We also know that clonidine does not do any of the above to any measurable or consistent extent although its use still has supporters and there is some promise of its chemical cousin, lofexidine (Brit-Lofex) for withdrawal symptoms. As yet, we still do not know whether the buprenorphine combination (bup-combo) drug is as effective as pure buprenorphine. There are indications that it is less efficacious (Bell) although another paper (Strain) showed contrary-wise that the combination drug caused consistently higher blood levels of 10-40% and thus might be expected to yield a better response. Thus readers may ask why use a combination drug rather than the pure drug, especially when the combination drug is not approved for commencement of treatment. The combination drug's only claimed benefit is reduced attractiveness to the street market. Yet dose diversion would not seem to be an issue here, being largely supervised and only short-term.

Unsurprisingly, the authors find that a higher proportion of bup-combo opioid dependent patients remained in 14 days of prescribed "detox" than those given no opioids. Also, and most importantly, they found that in-patients fared much better than out-patients in all respects (apart from hapless pair who perished in the in-patient group).

The authors fail to clearly define 'opioid detoxification'. Some might find the prescribing of opioids during 'detoxification' incongruous. Opioid detoxification cannot really commence until the patient ceases all significant intake of opioids. Even on day 13, these patients were offered 2mg of buprenorphine, still ten times the standard analgesic dose of 0.2mg sublingual (the maximum dose given - on day 3 - was 16mg). A further period of 14 days follow-up for the bup group might have allowed a fairer comparison of the two approaches in this case.

Either way, the authors have not clearly defined what they mean by detoxification, nor have they explained their statement in the abstract that 'success' involved an 'opioid-free urine sample on the last day of clinic attendance'. Perhaps their pathologist was unable to detect buprenorphine. Later in the article they state this must be free of *illicit* opioids, without defining *illicit*. Buprenorphine, like methadone, morphine or codeine can be licit or illicit. Indeed, it was to address the issue of diversion that the combination drug was introduced into the USA. Yet we now know that it can be abused, and that there is little if any evidence of less diversion than for other prescribed opioids.

In several countries now, even heroin can be legally prescribed and it is possible that, prescribed in decreasing doses, it might have comparable or better results than buprenorphine reductions. The very next item in Addiction is, in fact, a favourable comparison of oral morphine with methadone from experienced researchers in Austria.

Adverse events: The section on side effects starts out with a long, confusing, 'de Quincey-esque' sentence of 62 words. In the following 57 lines comes a tedious and confusing 'lecture' to the reader on the technical difference between 'serious adverse events' and 'adverse events'. Only at line 37, and after the reassuring statement 'Few serious adverse events occurred in either protocol' do we first learn of two deaths in this 14 day, 344-subject study. This implies a very high average mortality and requires some detailed explanation. All we are told is that one death (in the bup-combo group) was due to 'respiratory failure' (could this be 'code' for drug overdose?) and one was from the clonidine treated group ('bacterial endocarditis' - usually a slow or sub-acute disease in drug addicts). We are told (without coronial references) that 'neither death was attributed to study medication'. However, we are also told that patients in both groups took an average of three other medications during the trial, including 'OTC' acetaminophen (paracetamol), ibuprofen, loperamide and diphenhydramine as well as prescribed oxazepam, lorazepam, phenobarbital, hydroxyzine, methocarbamol, trimethobenzamide, Donnatal (containing phenobarb), zolpidem, trazadone and doxepin.

I have never heard of a patient dying whilst undergoing supervised detoxification from opioids, so these mortality reports need to be taken very seriously, especially when the patients were in a NIDA approved treatment protocol in registered and (presumably) accredited medical facilities. I can only speculate (as the authors do not) that this was a trial which attracted the most severely ill American addicts and/or may not have provided the best means to rehabilitation for their condition. Neither trial protocol is an 'evidence based' or proven modality for heroin addiction, even though both may be reasonable choices for subjects as long as they also have the option of more effective avenues such as traditional methadone maintenance. In many American (and Australian) cities there are still long waiting lists and/or methadone is beyond the financial reach of many addicts.

The authors state "In the out-patient group, 18 serious events occurred, with 14 in the bup-nx group and four in the clonidine group." Equal numbers of serious events occurred in the in-patient groups, including two with suicidal behaviour and one with persistent vomiting in those receiving bup-nx. I am mystified how an in-patient can have a 'motor accident' whilst under treatment, yet, along with 'spine surgery' we are offered this as an 'adverse event' without further explanation. It is also hard to understand how a patient who was assessed as suitable for detoxification could have died so quickly of sub-acute bacterial endocarditis. Detoxification is highly unwise in those with active septicaemia. One patient dropped out due to 'sensitivity to a study medication' (unspecified). This 'unfortunate' omission becomes a 'serious' one if buprenorphine were implicated.

The most important finding of this trial is probably that in-patient detoxification was so much more efficacious than community treatment (despite there being no randomisation). The differences were dramatic and they point up the inappropriate decisions made by successive administrations to close down drug and alcohol detoxification wards in New South Wales and elsewhere. Much of this was based on claims by so-called experts of their services not being 'cost-effective' or 'evidence based'. This trial shows that by using counselling and the Californian "Matrix" protocols and a 'placebo' such as clonidine, excellent in-patient detox results can be obtained in selected patients.

Comments by Andrew Byrne ..

Conflict of interest: Dr Byrne earns a proportion of his income dispensing methadone and buprenorphine to registered dependency patients.

Please note that Professor Charles O'Brien has written an excellent editorial in this 'Addiction' pointing out many of the above problems. Were he or I a reviewer, this month's edition might have been thinner.

Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction (2005) 100: 1090-1100

Encourage hepatitis B vaccination in those at risk

Aust N Z J Public Health (2005) 29;4:305-7

Rogers N, Lubman DI. An accelerated hepatitis B vaccination schedule for young drug users.

Dear Colleagues, This study offered a free 3-week hepatitis B vaccination schedule to drug users under 23 years of age who were attending an outreach service. Out of a total patient population of around 500, 90 young people were recruited to the trial, of whom 71% completed all three injections. A further 11% had 2 injections. This enviable rate is much higher than other reports quoted.

This trial shows that drug users are often willing to be involved in preventive health measures when these are offered. Since drug users are at high risk for viral diseases, we should be encouraging all involved to ensure that they have maximum protection. The Sydney injecting room might be another place where a strategy like this could yield enormous benefits.

comments by Andrew Byrne ..