The use of naltrexone implants as an 'exit strategy' from OMT.

This is a summary of Ross Colquhoun’s presentation, and the case studies, from our Concord Seminar February 2010, “The Exit Strategy Part 1”. Summary and comments from Richard Hallinan, and responses kindly provided by Ross Colquhoun (in capitals).


Ross Colquhoun described his own extensive experiences with ROD and naltrexone implants.

He reiterated that the implants can provide 6-12 months protection against heroin overdose. He explained that swellings at the site of naltrexone implants are usually due to an allergic reaction which can be treated with prednisone, and do not require antibiotics or removal of the implant as sometimes is done by medical doctors

RC mentioned the correspondence in MJA in 2009 (Degenhardt et al) reporting 12 cases of presentations to hospital emergency departments in Sydney following on naltrexone implant (it is not clear how many of these implants were performed at RC’s facility). RC argued, as did a number of correspondents to the journal, that the original report had failed to distinguish between ROD and implant-related symptoms.

COMMENT RC: ONLY ONE OF THE ADVERSE EVENTS RELATED TO AN IMPLANT (AN EXCLUSION) AND ALL THE OTHERS RELATED TO WITHDRAWAL FROM A DETOX OF ONE SORT OR ANOTHER AND WOULD HAVER HAPPENDED IRRESPECTIVE OF WHETHER THE PERSON HAD AN IMPLANT OR NOT

Comment RH: as the two procedures are performed together in these instances, it is indeed problematic attempting to distinguish the cause of severe symptoms when they occur. There is no research to indicate whether the implant itself might intensify the opioid withdrawal symptoms.

COMMENT RC: THERE IS A LOT KNOWN ABOUT NALTREXONE AND THE IMPLANT IS NALTREXONE DELIVERED OTHER THAN ORALLY. ON THE OTHER HAND ANYONE AT ALL FAMILIAR WITH WITHDRAWAL WOULD HAVE SEEN THE SAME SYMPTOMS PRE-IMPLANT ERA AND NOTHING HAS CHANGED. I HAVE DATA ON ALL THIS, WHICH I CAN MAKE AVAILABLE
IF WANTED

RC showed data from his published paper (Journal of Opioid Management 2005). He stated that he had followed a total of 43 patients who had received naltrexone implants compared with 41 who received oral naltrexone, with telephone self-reported (or reported by a contact person) heroin use clearly lower in the implant group than the oral naltrexone group. Asked whether this was therefore a prospective study with 100% follow up at 6 months, RC explained that the follow up was indeed very good and approaching 100%, though it fell off at 12 months (data unpublished as yet).

COMMENT RC: THIS DATA WAS INCLUDED IN THE PUBLISHED PAPER AND SOME 20% WERE NOT CONTACTABLE AT 12 MONTHS AND WERE NOT INCLUDED IN THE ABSTINENCE GROUP

Comment RH: my original reading of this paper was that it was retrospective, with the numbers in each group reflecting those who had been successfully contacted. Further data such as the denominator of all patients treated at the study centre in the time period would be needed clarify this important methodological question.

COMMENT RC: IT WAS NOT RESTROSPECTIVE, ALTHOUGH SUBJECTS WERE NOT RANDOMLY ALLOCATED TO EITHER GROUP BUT CHOSE TO HAVE AN IMPLANT OR TO TAKE ORAL NTX AT A TIME WHEN THERE WAS A MUCH SMALLER PROPORTION OF PEOPLE WHO CHOSE AN IMPANT. NOW IT IS WELL OVER 90%.

The protocol for managing ROD has evolved since Ross Colquhoun’s unit started doing it. Sedation with benzodiazepines (midazolam and flunitrazepam) is the mainstay, such that the person experiences but does not remember withdrawal symptoms. Naltrexone is given orally while the patient is sedated but not unconscious. This appears to precipitate opioid withdrawal much more profoundly than the obligatory naloxone challenge, which is however still given at some point during the procedure. Dexamethasone is now routinely given to prevent pulmonary edema, which previously occasionally happened during or after ROD. Octreotide has dramatically reduced gastrointestinal symptoms especially vomiting. Most patients are observed overnight by an experienced nurse.

Asked about accreditation, RC stated that the facility was not accredited by ACHS. However the doctors working there carried indemnity insurance, usually General Practice Level 1, which covers minor surgical procedures under sedation.

Dr Alex Wodak pointed to RC’s slide listing people he considered suitable for naltrexone implant. These included persons stable on MMT. Dr Wodak asked how this could be reconciled with the wording of the TGA Special Access Scheme A, under which Category A patients are defined as "persons who are seriously ill with a condition from which death is reasonably likely to occur within a matter of months, or from which premature death is reasonably likely to occur in the absence of early treatment". Specifically he asked how stable MMT patients could be considered reasonably likely to die within months. RC responded by pointing to the second clause, that heroin addiction is reasonably likely to cause death in the absence of early treatment, and rejected the claim that this was somehow using a “loophole” in the regulation.

Comment RH: one would have to ask whether stable MMT patients are seriously ill.

COMMENT RC: STUDIES FROM ENGLAND AND SCOTLAND INDICATE THAT DEATHS ASSOCIATED WITH METHADONE APPROACH 60-70%. FIGURES ARE NOT AVAIALBLE HERE, HOWEVER WE EXPECT THAT RATE TO BE COMPARABLE. METHADONE IS A HIGHLY ADDICTIVE AND DANGEROUS DRUG THAT CAN RESULT IN OVERDOSE AND DEATH ESPECIALLY WHEN USED WTH OTHER CNS DEPRESSANTS

In response to the query about the role of the TGA, Ross Colquhoun told the audience that the TGA approved of his use of category A for provision of naltrexone implant treatment, and that he had documentary evidence of this. He further stated that while he had had doubts about using Category A notification for naltrexone implants for alcohol dependence, the TGA had actually encouraged him to do so.

COMMENT RC: IN 10 YEARS THE TGA HAD NEVER QUERIED THE USE OF SAS PROVISIONS TO ENABLE US TO USE NTX IMLPANTS


In the second half of the seminar, two case studies were presented.

Acknowledging that Ross Colquhoun could provide many examples of people who had simply done very well with naltrexone implant, the cases presented were more complex.

The first was of a 26yo man (at the time of a naltrexone implant in mid 2009) who had first used heroin age 20, snorting then quickly IDU. He kept down responsible and highly paid work. His first MMT was 2005, and there was an unsuccessful transition to BMT from higher dose MMT in 2006, then MMT again till 2009. There was a strong family history of addiction, and the patient had previous problematic benzodiazepine use, with “panic disorder” treated by several GPs with benzodiazepines including oxazepam and alprazolam. During 2008 he had several driving offenses, including unlicensed driving x 3; and intoxicated driving causing an accident. His apparent inability to conceive a child led to stress with his partner, who was keen to have baby. He had hypogonadotrophic hypogonadism (very low testosterone 2-4 nmol/L), obesity, steatohepatitis and gynaecomastia while on MMT. During opioid treatment there was ongoing use of benzodiazepines, alcohol, stimulants (cocaine and amphetamines). He showed great impulsivity and enthusiastic suggestibility with marked inability to follow through on his resolutions, including investigation and treatment of his liver problems, infertility and hypogonadism, relapse prevention counseling, and psychologist counseling.

Discontent, and under duress from his wife (threatening divorce) and her parents (who offered to pay), he signed up for ROD and naltrexone implant, against advice from the treating addiction physicians. 10 days post implant insertion, he had the implant removed by a GP, owing to allegedly unbearable symptoms, despite being advised against removal by his addiction specialist and a public hospital. He relapsed into heroin use, spent a large settlement from his divorce on heroin, eventually returned to MMT. After another brief transfer to BMT he expressed discontent at not able to enjoy heroin, and sought MMT again.

This man died of a heroin overdose on 3rd day of MMT induction, having missed 2 days’ dosing.

The discussion started with the observation that this counts in the statistics as a death during methadone induction, but under the current reporting mechanisms in NSW, will not be connecting with ROD or naltrexone implant in any way. The question was posed whether naltrexone implant treatment had in fact destabilized this patient. From the floor came the comment that this patient could not have been called stable at any time. On the other hand, during previous MMT he was at least alive and working.

It was evident that the implant provider had not been made aware of the true extent of this man’s instability. The addiction specialists considered him unfit for implant on grounds of:
1. previous failure to achieve abstinence on MMT or BMT and his lack of commitment to opioid abstinence
2. ongoing other drug use
3. impulsivity
4. his being under duress to have the treatment
5. his underlying anxiety disorder.
6. his constant seeking for a quick, preferably chemical, fix to his problems.
7. his previous failure to engage in counseling

This case highlights the need for better lines of communication between providers of opioid pharmacotherapies and the providers of ROD and naltrexone implants.

COMMENT RC: IN THIS CASE HE GAVE FULL AND FREE CONSENT TO UNDERGO NTX TREATMENT AND WAS ABLE TO SUSTAIN A PERIOD OF ABSTINANCE FROM OPIATES. BEING PROFOUNDLY UNHAPPY WITH HIS LIFE AND HAVING TO RESUME MMT SUICIDE COULD NOT BE RULED OUT. IT IS EVIDENT THAT THE PERIOD ON NTX DID NOT RESULT IN HIS DEATH, ALTHOUGH PERHAPS INDIRECTLY AS HE REALISED HE WAS NOT ABLE TO SUSTAIN HIMSELF WITHOUT OPIATES AND THAT HE DETESTED THE NOTION OF HAVING TO REMAIN ON MMT FOR THE FORESEEABLE FUTURE. IN MANY WAYS HE WOULD BE NOT DISSIMILAR TO MANY WHO PRESENT FOR TREATMENT, BUT WHO THEN DO VERY WELL.
HIS OUTCOME WAS VERY UNUSUAL IN OUR EXPERIENCE.

The second case was of a 48yo professional dancer “Nelly M’Elba” who started her current episode BMT in 2002 after a prior 28 years heroin IDU, including several episodes of MMT. There were extended periods without heroin between periods of opioid treatment. There was regular THC use but little alcohol, and occasional use of stimulants especially cocaine. In 2004 Nelly did rapid detox with naltrexone implant and at last report still states “it was successful”. Although they were told that naltrexone was mainly good for alcoholism, but actually Nelly increased her alcohol to 60-75 g/day in the months after the implant. Nelly also got diazepam from the implanting doctor about 5/12 after the implant, and continued this until taking up heroin again after 10 months. 15-18 months after implant Nelly was worried about an unsightly lump interfering with her with dancing work. The implanting Dr was reported to be uncontactable, overseas. The addiction specialist discussed the case with the manufacturer, who stated such lumps are unusual, almost always disappear by 24 months post implant, and continue to release naltrexone while they are still not dissolved. If not dissolved by 24 months, the manufacturer suggested referral to surgical clinic for advice.

Three happy endings:
1. Nelly’s lump went way by 26 months.
2. Nelly’s best friend (and colleague) who had ROD and naltrexone implant at the same time, had a second implant and at last report was also back on buprenorphine treatment.
3. “Perry”, a naltrexone implant success story had had no heroin or benzodiazepines in 2 years. Perry showed Nelly his two 'expired' implants, 12 and 18 months old respectively, still prominent and unsightly, but he had been told they may take up to two years to dissolve. He was not worried in the slightest about the lumps, just happy to be free of drugs.

A less happy ending:
The implanting doctor in Nelly’s case is apparently still overseas. It was reported in the press that he had no legal representation throughout a court case in the NSW Supreme Court in which $6 million was awarded against him (in May 2009), in relation to brain damage sustained by a patient prescribed certain medications to withdraw from drugs. It was reported that he had no medical indemnity insurance at the time.
http://www.dailytelegraph.com.au/news/ex-junkie-wins-6m-but-wont-get-a-cent/story-e6freuy9-1225707964425

Comment RH: although the newspaper report is on public record, the precise circumstances regarding indemnity insurance are not. Nonetheless this case raises important questions about the need to ensure that people providing addiction treatment have an appropriate level of indemnity insurance; this is particularly important for treatment which are unapproved or lack published evidence, and for the use of TGA-unregistered treatments.

As to cost, ROD procedure is $7800, with implant $5600. A subsequent implant requiring no ROD costs $1400. Ross Colquhoun made the point that this is a low cost, compared with the alternative possibility of many years of opioid agonist treatment with no “Exit Strategy”.

The subject of the “Exit Strategy” for methadone and buprenorphine maintenance treatments will be taken up in the second seminar on this subject, in December 2010.

References

Colquhoun R, Tan D, Hull S. A comparison of oral and implant naltrexone outcomes at 12 months. J Opioid Manag. 2005 Nov-Dec;1(5):249-56.