Methadone tolerance testing in drug misusers

Risk of undertreatment

Unless planning to detoxify, patients with high tolerance need high doses of methadone. If the substituted amount of methadone is less than their opiate habit, addicts will usually top up with illicit heroin, methadone, or benzodiazepines until they have reached adequate maintenance doses. Postmortem studies of deaths during methadone induction have detected the presence of alcohol, benzodiazepines, and other substances in most cases.2 7 8 10 Thus, these deaths may result not from the methadone itself but from misuse of these other drugs. Undertreatment with methadone could, paradoxically, increase the risk of toxicity.

A systematic review of randomised controlled trials has shown that higher methadone doses (60-100 mg/day) are more effective than doses under 60 mg in both retention on maintenance treatment and reduction of illicit drug use.11 It is difficult to randomise for methadone doses greater than 100 mg, but evidence exists that outcomes continue to improve with use of higher daily doses in those that need them. For example, a controlled trial found that among 164 patients who were clinically unstable on 100 mg methadone, increasing the dose to 120-780 mg (average 211 mg) daily resulted in better treatment retention and less illicit drug use than among the control group of 101 randomly selected patients on daily doses of 10-100 mg (average 69 mg) at the same centre.12

UK national guidelines recommend doses 60-120 mg as most effective but do not give a maximum dose.13 Yet nearly 75% of British primary care methadone prescriptions are for doses less than 40 mg.14 In a primary care survey of 204 methadone maintenance patients the drop-out rate was 50% after one year of treatment.15 Thirty seven per cent of those who dropped out left because of underdosage or rigidity of the appointment systems, while 33% were expelled for misdemeanours such as urine samples testing positive for illicit drugs. Highly tolerant patients most in need of treatment are thus least likely to receive it.

Testing methadone tolerance

At Lisson Grove Health Centre (an inner city general practice with 7500 patients), we try to overcome this problem by testing methadone tolerance to tailor the patient's starting dose to their usual opioid intake. Our philosophy is to facilitate treatment for opioid addiction as much as possible. Thus, we offer same day appointments, and any opioid addict entitled to NHS care and living in our catchment area can enter treatment promptly. Our assessment procedure follows national guidelines (see bmj.com).13 If we consider methadone maintenance appropriate and the patient consents, we test tolerance at the first opportunity.

Careful questioning of patients about the drugs used and the existence of true opiate withdrawal is vital. The dose given is based on the patient's experience with street or prescribed methadone—that is, the dose a patient says will “hold” him or her. In patients who have not previously taken methadone, we avoid using doses over 40 mg for tolerance testing. However, illicit methadone is so common in the United Kingdom that we rarely see addicts who have not used it. Addicts often use benzodiazepines intermittently to treat withdrawal symptoms. We explain that if the methadone dose is right, they should not need benzodiazepines.

A local pharmacy supervises the first dose of methadone at an arranged time. The patient is instructed to return immediately to our practice to be observed for signs of toxicity. Box 1 details the steps we take to reduce the risks of tolerance testing. Naloxone is available in case of intoxication but has never been needed in the 10 years we have used this approach. Patients are informed of the risks and signs of methadone toxicity. If there are no signs of intoxication, this dose of methadone is continued under the daily supervision of the pharmacist and a review is arranged within a few days. We do not allow patients to take drugs away until illicit use is reduced as shown by opiate negative urine samples, self report, and other data. One of our patients remains on supervised consumption after 12 years for this reason.

Box 2 gives the outcomes of our experience of testing for methadone tolerance. We believe this procedure may improve treatment uptake even for highly tolerant or high risk addicts who failed to engage with other services. For instance, we know of no primary care methadone programme engaging similarly high proportions of homeless people, a group with high risk behaviours16 and twice the risk of dropping out of treatment.15 Injecting drug users are another high risk group. They form a higher proportion of our patients (82%) than the average (68%) for services in our area (Westminster).17

Toxicity during methadone induction

Like all long acting drugs, methadone can accumulate and cause delayed toxicity. High starting doses of methadone and dose increases during titration, as well as low tolerance and drug interactions, have been thought to cause toxicity during the first two weeks of treatment.7 8

Safeguards in testing methadone tolerance

We matched the starting dose of methadone to the patient's tolerance and, despite using starting doses of up to 150 mg of methadone, did not encounter any methadone related toxicity or deaths in our case series. However, accumulation of this long acting drug and its delayed toxicity remain potential hazards, and we take safeguards against this (box 1). Our audit cannot quantify the safety of testing methadone tolerance compared with other induction methods. Induction deaths are expected in 0.2% at most,8 and our numbers are thus too small. We therefore recommend a rigorous trial to compare methadone tolerance testing with conventional induction methods.

Our experience is that patients do not undertake methadone tolerance testing for a dose they have not used before and for which they cannot predict the effect. Our patients know they will be observed and that naloxone will be used if needed. In practice, patients' judgment of their dose requirement has proved accurate, and patients do not like to risk showing themselves intoxicated by the dose they ask for. Addicts who request high doses are likely to be those who neuradapt most readily and are thus least likely to succumb to accumulation. Interestingly, despite our use of starting doses that the General Medical Council might well consider irresponsible, the only drug related deaths in our series occurred after methadone had been discontinued.