8 August 2003

Smoking cessation randomised controlled trial using gums, clonidine or naltrexone

Ahmadi J, Ashkani H, Ahmadi M, Ahmadi N. Twenty-four week maintenance treatment of cigarette smoking with nicotine gum, clonidine and naltrexone. J Subst Abuse Treat (2003) 24;3:251-255

Dear Colleagues,

This paper describes a simple three-way pharmacotherapeutic intervention for smoking cessation using nicotine gums, clonidine or naltrexone. In three randomised groups each of 60 would-be quitters, these researchers gave double blind treatments to see how many folk dropped out and how many managed to abstain from smoked nicotine over a six month period.

The results are of great interest and relevance to clinical practice, confirming some things we believed and showing some other novel findings. After 24 weeks of the study, abstinence rates were 37% for the nicotine gum group, 19% for the clonidine group and 5% for those given naltrexone, each finding being significantly different from the others.

The authors state that this supports the use of NRT (nicotine replacement therapy) and at the same time questions the utility of naltrexone for smoking cessation, which had mixed reports from previous literature reports.

The rate of significant side effects was 42% in those on NRT, 32% for clonidine and 84% for those taking naltrexone tablets (50mg daily). These were largely headache, GI upset, and sleep disturbances. Some of the 'side effects' may have been nicotine withdrawals.

It would seem that naltrexone has been tried for many conditions including anorexia and bulimia. I have prescribed it with consent for severe cannabis dependence patients with mixed results. Despite its consistently good results with alcoholism, other substance or behavioural disturbances seem less amenable to its antagonist effects.

comments by Andrew Byrne ..

Heroin trials - old and new.


van den Brink W, Hendriks VM, Blanken P, Koeter MWJ, van Zwieten BJ, van Ree JM. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 2003;327 310-0

Dear Colleagues,

It is fascinating to track the history of heroin prescription over the past 25 years. We first find an English report in an American journal. Next, almost 20 years later came another English description in an Australian journal. After that the major Swiss trials were reported in Anglo-American journals while this latest Dutch trial is in the BritishMedical Journal. It is indeed a global problem.

Most of these trials took treatment resistant heroin addicts and permitted pharmaceutical heroin to be injected with supervision under trial conditions. Some used comparisons with methadone but one used a six month delay as a 'chronological control' group. Patients were permitted realistically high doses of heroin, consistent with their pre-treatment street use, up to one gram daily. There were small trials of 30 to 50 patients such as Perneger and Hartnoll, while the main Swiss trial enrolled 1146 subjects.

There was a practice of prescribing morphine and heroin to addicted patients in the US, England and probably Australia prior to the 1940s but records have been lost and details are mired in history and even mythology. The Swedish prescribing of stimulants in the 1960s was similar in some ways. There appeared to be no prominence of adverse reports from coroners or others at the time but little else can be gleaned from a scientific stand point. There were reports of rapid opiate detoxification (bromides) under sedation from Hong Kong in the British Medical Journal of 1899 and at least one death was reported from that era.

The report by van der Brink and colleagues in the British Medical Journal describes 550 methadone patients who were still using illicit heroin in 6 Dutch cities. They were randomised either to remain in methadone treatment or to receive heroin (injectable if they usually injected, inhaled powder if they normally inhaled - making two separate trials). Despite being allowed up to a gram per day in three divided doses, patients chose to take only half that in an average of 2 daily supervised doses. The mean methadone dose was around 70mg daily, with a maximum permitted of 150mg. Although higher than average doses in some areas, this was probably still inadequate, just as occurs with methadone patients in every country.

Follow-up rates were as high as 95%. Outcomes of numerous aspects of social, mental and physical integration were examined by independent researchers using a modified Addiction Severity Index (ASI). Improvements were marked in both groups but almost twice as much in the groups permitted heroin as well as methadone (~45% vs. ~25% 'response' rate = 40% improvement in ASI). The differences were significant. The rather unfortunate end to the trial was a compulsory 2 months without prescribed heroin, during which the good progress was reversed.

Those decrying a heroin trial in Australia are just delaying the inevitable while the consequences of unchecked drug use cause untold damage to the security and prosperity of our community. There has been no report of increased drug addiction or other adverse sequelae of drug use in regions where heroin has been prescribed. Also, in the largest and longest controlled trial in Switzerland, only a small expansion has occurred, disproving any 'floodgates' effect. Politicians should note that a referendum on such policies was resoundingly successful, especially in the older age groups.

Comments by Andrew Byrne ..

Hartnoll RL, Mitchelson MC, Battersby A, Brown G, Ellis M, Fleming P, HedleyN. Evaluation of Heroin Maintenance in Controlled Trial. Arch Gen Psychiatry1980 37:877-84.

Metrebian N, Shanahan W, Wells B, Stimson GV. Feasibility of prescribinginjectable heroin and methadone to opiate-dependent drug users: associatedhealth gains and harm reductions. 1998 Med J Aust 168:596-600

Perneger TV, Giner F, del Rio M, Mino A. Randomised trial of heroinmaintenance programme for addicts who fail in conventional drugtreatments. BMJ 1998;317:13-18

Ali R, Auriacombe M, Casas M, Cottler L, Farrel M, Kleiber D, et al.Report of the external panel on the evaluation of the swiss scientificstudies of medically prescribed narcotics to drug addicts. Sucht1999;45: 160-70

Rehm J, Gschwend P, Steffen T, Gutzwiller F, Dobler-Mikola A,Uchtenhagen A. Feasibility, safety, and efficacy of injectable heroinprescription for refractory opioid addicts: a follow-up study. Lancet2001;358: 1417-20

Haemmig RB, Tschacher W. Effects of high-dose heroin versus morphine inintravenous drug users: a randomised double-blind crossover study. JPsychoactive Drugs 2001 Apr-Jun;33(2):105-10

Spanish group's experience with naltrexone implants.

Spanish group's experience with naltrexone implants. 'AddictionBiology' report.

Maintenance treatment with depot opioid antagonists in subcutaneousimplants: an alternative in the treatment of opioid dependence. Carren JE,Alvarez CE, San Narciso GI, Bascaran MT, Diaz M, Bobes J. Addiction Biology(2003) 8, 429-438

Dear Colleagues,

In this paper a group of Spanish naltrexone enthusiasts report on 156patients, nearly all male, who were treated with a rapid opioiddetoxification process followed by a naltrexone implant. It is due to the‘open’ policies of the editors of Addiction Biology that they are preparedto publish such papers. Research of this nature would be unlikely tosurvive the strict new ‘Farmington’ editorial rigours of the NAC ‘sister’journal, Addiction, edited by Griffith Edwards.

These researchers’ main finding is a two year follow-up with 4 six-monthlyretention rates of 80%, 65%, 55% and 21% “all of them remaining abstinent toopioids.” “It is concluded that the programme is safe for the patients andshows a better retention index than programmes using oral antagonists, withan improved compliance (negative urine analysis) compared to the latter.”Thus, although 80% of patients are lost to follow-up the authors seemconfident to report comparative results.

The authors also allow us to compare these naltrexone treated patients withthose prescribed methadone. Their reported statistics show only very minordifferences in social, drug use and other demographics over the 24 monthsfrom starting the treatment. This is in stark contrast to methadone andbuprenorphine patients who generally report dramatic and sustainedimprovements in employment, housing, drug use and criminal statistics afterjoining treatment. Indeed, despite finding a worrying increase in alcoholconsumption (mean 50%) over the period, the Spanish authors do not address this.It is also unfortunate that the authors of this naltrexone study do not givetheir specific clinical indications for the use of an experimental treatmentin preference to methadone or buprenorphine treatments which are the normal ‘gold standards’ for unstable opiate addiction in most western countries. At one point they give the feeble and almost embarrassing information thatnaltrexone is beneficial over methadone because it has no drug interactions,apart from the obvious one (the effects of opioids are negated in patients on naltrexone).

In our practice we have prescribed naltrexone to many patients over the years with a small number doing well for limited periods taking the oral formulation. Our indication for the use of naltrexone is for stronglymotivated patients seeking abstinence and who have faired poorly on agonist treatments. There is also a proportion of addicts who refuse to takemethadone and buprenorphine but their success rates on naltrexone do not seem to be any better than the others, the majority relapsing after stopping the medication, whether oral or implanted.
There may be sub-groups who do well with naltrexone but as long as research is done by ‘enthusiasts’ for the treatment in an undiscriminating manner, we will never learn what those subgroups are. Only randomised controlled research can resolve this question and the few such trials that there are to date using naltrexone are not encouraging for its use in non-selected opioid dependent patients.

Comments by Andrew Byrne ..

BMJ report on less methadone ampoules/tablets but more oral liquid prescribed over 12 years

Strang J, Sheridan J. Effect of national guidelines on prescription of methadone: analysis of NHS prescription data, England 1990-2001 BMJ (2003) 327: 321 - 322

Dear Colleagues,

This intriguing item claims to examine the results of published English clinical guidelines yet it only examines 2 minor outcomes, and then not how these were achieved. On examining NHS prescriptions the authors found that the use of methadone tablets and ampoules had dropped by around 50% in a decade. Without examining clinical details, they assume that both of these outcomes were favourable, and that further, the changes were necessarily a result of their own published dependency guidelines which were circulated to GPs in 1996 and in 1999 (see title of article). The number of prescriptions for methadone overall increased, each year, albeit unevenly, tripling over a 12 year period to 2001. We are not told the duration of such prescriptions, nor what proportion of patients were in continuous maintenance treatment or detoxification regimens.

The same issue of BMJ contains a positive descriptive item on prescribed heroin from Holland, so injectable methadone may equally have a place in legitimate clinical practice. It was reported that less than 10% of all treatment in England utilises injectables. Methadone tablets, likewise, may have a useful if small place in dependency treatment where other measures have failed. Hence a blanket edict against such treatment may not be appropriate, despite neither tablets nor ampoules being standard, evidence-based approaches.

It is disappointing that these veteran researchers, while giving a small glimmer of potentially good news, ignored an examination of the dose levels on these prescriptions as well as the degree of supervision given, or not given. Their own guidelines recommend 60mg as a minimum effective daily dose for most patients, yet it is said that *average* doses in England are below 50mg daily. Very little methadone in England is taken under supervision, although the words ‘supervise’ or ‘supervision’ are used up to 50 times in the ‘Orange Guidelines’, written by a panel chaired by Strang.

Many pharmacists in Scotland now regularly supervise methadone doses as recommended in Strang’s highly regarded guidelines. It is possible that the Scots even go ‘too far’ in daily dose supervision, just as English pharmacists seem to avoid it altogether for obscure reasons. The nature of addiction involves a lack of control over drug use, thus making supervision an important plank of any treatment strategy. It is disappointing that the originators of these impressive dependency guidelines have still not stated in unequivocal terms that their many English colleagues are systematically undermining good clinical work by ignoring evidence and giving poor quality treatment to their patients. In certain cases it may be worse than giving no treatment at all. Improved treatment would simply require endorsing prescriptions with a careful but adequate dosing schedule - and a request for a certain proportion of doses to be ‘supervised’.

Comments by Andrew Byrne ..