Failure of naltrexone implant reported from Russia.

Dear Colleagues,

Griffith Edwards, long time Addiction editor, once wrote that case reports were of limited value scientifically - and he was right. However, sometimes simple clinical observations can be the start of something big, such as lithium on the positive side (Melbourne) and thalidomide (Sydney) on the negative one.

In this month�s Addiction (July p1164) Krupitsky, Woody and colleagues report on a patient who overcame the artificial blockade from a naltrexone implant, a product which is apparently now registered for use in Russia [1 gram ~ �one month blockade�].

A drug dealer engaged the patient as a courier, knowing that he had had an implant. He assumed that the man could therefore not avail himself of the large quantities of drugs he was to smuggle into a local prison on a regular basis.

After receiving numerous payments in the form of heroin he attempted to �test� the blockade by injecting first 2, then 4, then 8 and then even more �bags� of the illicit heroin. We are told that on the final injection he overdosed and became cyanotic. Having survived, he continued using the by now very large quantities of heroin until it ran out 2 weeks later. Suffering severe withdrawal symptoms, he was then re-admitted for detoxification. It is a mystery that methadone treatment is still illegal in the Russian Federation, yet an unproven formulation of naltrexone is being used by �narcologists�.

Detoxification only rarely results in abstinence for life and it is tragic that relapsing addicts in Russia have little alternative but to return to street opioids.

Doctors who use naltrexone implants in addiction treatment are taking risks both for themselves and their patients. The benefits of naltrexone implants might outweigh their very real dangers, yet no comparative research has yet been published to support their use. Since most return to heroin use at some stage, those recommending naltrexone need to propose strategies to prevent overdoses. After detoxification, there is very low tolerance and thus heightened vulnerability to overdose.

Hulse and Tait, who are usually strong advocates of naltrexone and these days are strong advocates of naltrexone implants, draw attention to another serious problem with naltrexone implants. Because opioids are generally ineffective at normal doses, some patients will die from overdose of combinations of non-opioid drugs (or from spectacularly high doses of opioids as above) (Hulse GK, Tait RJ. Opioid overdose deaths can occur in patients with naltrexone implants. MJA 2007 187;1:54). However, their estimate in the same letter that the mortality of patients on naltrexone implants is only one in 600 patient-years seems a tad optimistic and should not be accepted until replicated by others in well-designed studies. We have to be mindful that naltrexone supporters in Australia and overseas have often �over sold� the benefits while also under-estimating the negatives of naltrexone. Remember 'I woke up cured of heroin addiction' in the Woman's Weekly a decade ago?

Comments by Andrew Byrne ..

Krupitsky EM, Burakov AM, Tsoy MV, Egorova VY, Slavina TY, Grinenko AY, Zvartau EE, Woody GE. Overcoming opioid blockade from depot naltrexone (Prodetoxon�). Addiction 2007 102:1164-5

Hulse GK, Tait RJ. Opioid overdose deaths can occur in patients with naltrexone implants. [response] MJA 2007 187;1:54

Gibson AE, Degenhardt LJ, Hall WD. Opioid overdose deaths can occur in patients with naltrexone implants. MJA 2007 186;3:152-153

June Addiction journal: solid studies but a new 'sting in the tail' like Scorpio.

Dear Colleagues,
It is nice to see the Addiction journal finally giving some prominence to harm reduction. There is an item on secondary benefits of injecting rooms as well as two brief reports questioning current policies and institutions (see below, from Australia and Canada). Compiled by Peter Miller and Susan Savva, the �News and Notes� column has been known to toe the zero tolerance line, even rubbishing those who might question prohibition (eg. Aug 2000) or support medical cannabis.
It is hard to understand why the National Addiction Centre and Society for the Study of Addiction have never conceded the parlous stage of dependency treatments and harm reduction measures in the UK. They both seem to studiously avoid controversy and continue doing �more of the same�. Even to this day, the SSA internet notice board which took about 8 years to get up and running carries no traffic.
Is there no-one in England with enthusiasm for our important and interesting field? Are people so intimidated or embarrassed at previous failures that they have gone underground or moved overseas?

Comment by Andrew Byrne ..

ADDICTION JUNE 2007 "News and Notes"

AUSTRALIAN CRIME COMMISSION CONCLUDES PROHIBITION �NOT EFFECTIVE� [What a surprise!!]

The Age newspaper in Australia features a report [1] on the Federal Parliamentary Joint Committee on the Australian Crime Commission. Their recent �Inquiry into the manufacture, importation and use of amphetamines and other synthetic drugs in Australia� [2] has concluded that: �prohibition, while theoretically a logical and properly intentioned strategy, is not effective�. This conclusion didn�t sit easy with the current Australian government and The Age suggests the sensationalised climate that politicians have to work within makes them fearful of entering a rational debate on drugs.

References

1. Andrew Macintosh, 20 March 2007. Sensationalism no way to fight drug addiction. Available online: http://www.theage.com.au/news/opinion/sensationalism-no-wayto-fight-drug-addiction/2007/03/19/1174152967041.html
2. Parliamentary Joint Committee on The Australian Crime Commission (February 2007) Inquiry into the manufacture, importation and use of amphetamines and other synthetic drugs (AOSD) in Australia. Available online: http://www.aph.gov.au/senate/committee/acc_ctte/aosd/report/report.pdf

INCB [International Narcotics Control Board] �CLOSED TO REASON�

The Canadian HIV/AIDS Legal Network and the International Harm Reduction Development Program, joined by former United Nations Special Envoy for HIV/AIDS in Africa, Stephen Lewis, held a press conference in March this year to release �Closed to Reason: The International Narcotics Control Board and HIV/AIDS�. The new report details the ways in which the INCB, funded and staffed by the UN, has blocked effective HIV prevention for injecting drug users. The document focuses on errors of fact and omissions in International Narcotics Control Board (INCB) publications and statements, the ways in which the Board has ignored expert legal counsel and scientific evidence, and calls for greater accountability and transparency.
The key finding of the report was that the role of drug policy has been transformed since the era in which the International Narcotics Control Board was founded. It concludes that the Board has become an obstacle to effective programs to prevent and treat HIV and chemical dependence. The authors found that INCB annual reports are rife with omissions and misrepresentations and lack both scientific documentation and justification for legal opinions. They criticise the reports for praising governments that violate human rights, such as Thailand and China.
�Closed to Reason� recommends improved accountability for the INCB and calls for the World Health Organization, the UN Economic and Social Council and UN member states to ensure that the Board includes persons with expertise in HIV/AIDS policy and international law. For the full report in English, please visit: http://www.aidslaw.ca/drugpolicy or http://www.soros.org/harm-reduction

ADDICTED TO TANNING?

The website Medical News Today reports that despite repeated health warnings about the dangers of tanning from sunlight and artificial light sources, there are still those whose mantra �bronzed is beautiful� remains unshaken [1].
<snip>

Reference:

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. Addiction 2007 102;6:916-9

Data Do Not Support Buprenorphine as a First-Line Treatment for Addiction

Byrne A, Wodak A. Data Do Not Support Buprenorphine as a First-Line Treatment for Addiction. American Journal of Psychiatry 2007 164;11:1757

Letters to the Editor

American Journal of Psychiatry 164:11, November 2007 ajp.psychiatryonline.org 1757 �Data Do Not Support Buprenorphine as a First-Line Treatment for Addiction�

TO THE EDITOR: In the May 2007 issue of the Journal, Johan Kakko, M.D., et al. reported on an excellent randomized controlled trial of �stepped� buprenorphine versus methadone therapy for heroin dependence (1). However, nearly two thirds (65%) of the subjects were transferred to methadone because of continuing illicit drug consumption or cravings. Therefore, this study suggests that methadone should be the drug of first choice for maintenance treatment, and buprenorphine should be reserved for patients who do not respond well to methadone.

Most trials to date have reported that methadone provides superior retention (2). Methadone is also less expensive and easier and faster to administer than buprenorphine and is accepted as a safe treatment during pregnancy.

Dr. Kakko et al. reported a nonsignificant difference in their primary outcome of 6-month treatment retention, with 77% for buprenorphine and 79% for methadone. Such high retention is unusual for trials of this kind. In addition, the high buprenorphine retention may have been partly achieved by a more rapid dose escalation and a higher mean dose (29 mg/day) than usual.

Before the findings of Dr. Kakko et al. are accepted, there should be confirmation of the �noninferiority� of a standardized buprenorphine regimen in a community rather than clinic setting.

Methadone is more toxic than buprenorphine. This finding may not have been apparent in the study conducted by Dr. Kakko et al., since most of their patients ultimately received methadone. In some jurisdictions, buprenorphine is already the most frequently prescribed maintenance therapy for opioid addiction. It is undoubtedly an excellent second-line treatment.

Another important finding in this study was the average dose of 29 mg/day, which is more than double the average in most other studies and almost the manufacturer�s maximum recommendation of 32 mg/day. Such a large dose often takes more than 15 minutes to administer. Dr. Kakko et al. speculated that the inclusion of naloxone (not naltrexone as stated in the editorial accompanying the article) in the combination product may have contributed to the need for such an unusually high dose. Other studies have reported higher doses required for the buprenorphine-naloxone combination (3). However, we are not aware of any rigorous �equivalence� studies comparing buprenorphine with the combination product.

The recommendation by Dr. Kakko et al. that buprenorphine should be considered as the first-line medication, despite 65% of patients being transferred to methadone, is difficult to accept. While industry support is often integral to the development of new intervention strategies, it has also been shown that studies funded by the pharmaceutical industry have a greater likelihood of reporting favorable conclusions (4).

References

1. 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; 164:797�803

2. Mattick RP, Kimber J, Breen C, Davoli M: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. The Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD002207

3. Bell J, Byron G, Gibson A, Morris: A pilot study of buprenorphine-naloxone combination tablet (Suboxone) in treatment of opioid dependence. Drug Alcohol Rev 2004; 23:311�318

4. J�rgensen AW, Hilden J, G�tzsche PC: Cochrane reviews compared with industry supported meta-analyses and other metaanalyses of the same drugs: systematic review. BMJ 2006; 333:782. Epub 2006 Oct 6

ANDREW BYRNE, M.D. Redfern, NSW, Australia ALEX WODAK, M.D.

Darlinghurst, NSW, Australia

Dr. Byrne owns and runs a private clinic that dispenses methadone, buprenorphine, and other drug treatment. Dr. Wodak is the director of a public clinic (free to patients and government funded) that dispenses both methadone and buprenorphine.

This letter (doi: 10.1176/appi.ajp.2007.07071058) was accepted for publication in July 2007.

Dr. Heilig Replies

TO THE EDITOR: Buprenorphine and methadone are both effective treatments for heroin dependence (1). Counting studies on these medications is obviously not a valid method for comparing their efficacy. For retention in treatment, a metaanalysis yielded only a tendency-level advantage for methadone in high-dose studies (relative risk=0.79; 95% confidence interval [CI]=0.62�1.01) (1). In flexible-dose studies, the relative risk was similar, but reached significance (relative risk=0.82; 95% CI=0.69�0.96). For drug use and criminality, the two treatments were reported to be equivalent. Thus, methadone provides a slight advantage over buprenorphine for retention in treatment, and the two medications are equivalent on other relevant outcomes.

Methadone treatment is essential, but also has distinct limitations. As pointed out by Drs. Byrne and Wodak, methadone is �more toxic,� i.e., methadone has sufficient mu-opioid receptor activity to induce lethal respiratory suppression, whereas buprenorphine, a partial agonist, does not. Safety itself aside, the monitoring necessitated by methadone use somewhat detracts focus away from building a therapeutic alliance, which offsets the cost advantage of the medication.

Given the complementary profiles of the two medications, pitching one against the other is not meaningful. The field needs rational ways of using both. In this context, we are unaware of any other therapeutic area in which a safer, albeit somewhat less effective medication, would be reserved for second-line treatment. Optimal balance between efficacy and safety is typically achieved by doing exactly the opposite. For example, few would consider using chloramphenicol for an infection before trying penicillin.

But what if stepping up treatment as needed rather than giving everyone methadone right away led to losing more patients overall? That would indeed mean that the safety gains must be carefully weighed against efficacy losses, an exceedingly difficult tradeoff. Our study was designed to assess whether this is a concern and clearly showed that it is not. Nothing is lost by first trying the safer medication.

In that perspective, the exact proportion of patients who ultimately transfer to methadone is irrelevant. But let us be correct. In our study, among 48 subjects randomly assigned to stepped treatment, 37 remained. Of those, 20 transferred to methadone. That is 54%, which is what we reported. The 65% given by Drs. Byrne and Wodak is a misrepresentation of our data.

In summary, excellent outcomes can be achieved by starting every heroin-dependent patient with buprenorphine and progressing to methadone only if needed. These outcomes are as good as those achieved with the best possible methadone treatment. Among unselected individuals addicted to heroin who are retained in treatment, close to one-half do well without progressing to methadone. Each of these individuals represents a safety gain worth capturing.

Finally, our study disclosed an unrestricted research grant from industry that accounted for approximately 25% of the budget. The remaining funding came from the Swedish Government and Stockholm County. It is unclear how this could invalidate our results. The reference cited (2) by Drs. Byrne and Wodak in support of this notion deals with meta-analyses, which our study clearly is not.

References

1. Mattick RP, Kimber J, Breen C, Davoli M: Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst Rev 2003;2: CD002207

2. J�rgensen AW, Hilden J, G�tzsche PC: Cochrane reviews compared with industry supported meta-analyses and other metaanalyses of the same drugs: systematic review. BMJ 2006; 333:782 MARKUS HEILIG, M.D., PH.D.

Bethesda, Md. Stockholm, Sweden

Dr. Heilig�s disclosures accompany the original article. [CME Disclosure: Dr. Heilig and Ms. Svanborg received research and travel grants from Schering-Plough. Dr. Nilsson has consulted for Merck. Dr. Kakko has received honoraria from Schering-Plough Estonia, Schering-Plough Sweden, and Reckitt Benckiser Australia. The other authors report no competing interests.]

APA policy requires disclosure by CME

This letter (doi: 10.1176/appi.ajp.2007.07071058r) was accepted for publication in July 2007.