Evaluation of levo-alpha-acetylmethdol (LAAM) as an alternative treatment for methadone maintenance patients who regularly experience withdrawal: a pharmacokinetic and pharmacodynamic analysis. Newcombe DA, Bochnera F, White JM, Somogyi AA. Drug and Alcohol Dependence (2004) 76; 1: 63-72
Dear Colleagues,
The Adelaide University Department of Experimental Pharmacology continues to impress with detailed scientific work which contains practical lessons for clinical practice.
In this study 16 volunteer methadone patients were transferred to LAAM (L-acetyl methadol, a chemical cousin of methadone, no longer in clinical use) for 3 months and then returned to methadone. While half the patients were chosen as stable or ‘holders’, the rest ‘non-holders’ based on ‘self report’, presumably of illicit drug use and/or withdrawal symptoms. The non-holders had a mean methadone dose of 83mg daily, the ‘holders’ 73mg, at the start of the study (an Adelaide study reported 63mg in 1996). Doses after the study were only very slightly higher with adjustments as clinically indicated during the 6 month period.
It is a disadvantage of pure experimental pharmacology studies using clinical subjects in treatment that one cannot easily determine whether treatment given was consistent with current guidelines (eg. Strang’s UK ‘orange’ guidelines). It is unlikely that a dose of 30mg in a ‘non-holder’ would be based on such prescribing guidelines which recommend about 60mg as a minimum effective dose to abolish withdrawals in most patients. Yet one such patient was included in this trial.
The researchers performed numerous clinical measures including pupils size, respiration rates, blood levels over 24 hours, but the most important findings were patient self report of satisfaction with the treatment (described here as 'holders').
Even with a randomised protocol it may not be possible to know if the improvements reported are due to the LAAM or the actual experimental “fuss” involved. But it does demonstrate that ‘non-holders’ can become ‘holders’ if alternative doses, drugs and/or other therapeutic interventions are considered in the therapeutic milieu. This same benefit can be seen with alternative prescribing in diverse branches of medicine such as arthritis, migraine and diabetes where sometimes a change in medication can lead to improvements for unknown and unpredictable reasons. The ‘placebo effect’ is probably responsible for some such reported benefits, yet actual differences must play a role as well.
Vincent P. Dole, who first devised methadone maintenance treatment, often reminds us that methadone is just another prescribed drug for a medical condition. When given in sufficient doses with adequate supervision and psychosocial supports, the results should be predictable and gratifying for both doctor and patient. But a proportion cannot or will not take methadone so, without an alternative, they drop out of ‘mono-therapy’.
It would be interesting to know how these researchers would approach a similar study, using 2 parallel groups of diabetics who were ‘stable’ and ‘unstable’ with regards to sugar levels. Often ‘real world’ clinical medicine is simpler than all of this science and utilises two principles: (1) patient choice and (2) trial and error (doctor’s choice) ... starting with the safest, cheapest or most popular drug, eg methadone and then only reverting to LAAM, buprenorphine, long acting morphine, naltrexone, etc in those who do not respond to the traditional drug in ‘full’ or adequate doses. And such simple measures, with adequate psychosocial supports, very often yield excellent results with up to 95% of subjects reportedly able to cease injecting behaviours, according to Dole.
While not directly related to this study, it is regrettable that LAAM, being a second day administered drug, was over-used in the United States for the convenience of clinics rather than for genuine clinical indications. The withdrawal of Vioxx for arthritis has some similarities (see also this week‘s JAMA for discussions of post marketing surveillance http://jama.ama-assn.org/). Both Vioxx and LAAM were found to have a very rare but potentially serious side effect (on heart conduction regards LAAM) and both are now completely withdrawn from the market in most countries. This was probably done to protect drug companies from legal liabilities without an independent examination of the risks and benefits in clinical uses. The drugs would probably still be indicated as valuable ‘second-line’ agents where methadone or other first line agents were found to be ineffective or to have unacceptable side effects. Even thalidomide has some limited uses despite its disadvantages. In most cases LAAM would be much safer than injected street heroin!
Comments by Andrew Byrne ..
