North America is experiencing a surge in the incidence of prescription opiate misuse and abuse. As more and more methadone maintenance programs are initiated to address this situation, family physicians will be increasingly required to deal with the methadone-maintained patient.

Methadone is a long-acting synthetic opioid agonist that was developed in WWII for battlefield analgesia. In its pure form, it's a white, odourless crystalline powder that is soluble in water. Today, methadone may be used clinically as a substitute drug in opioid dependence therapy, in opioid withdrawal management and as a long-acting analgesic for moderately severe to severe pain. Even if you don't prescribe the drug yourself, there's a good chance that you see patients in your office who are on methadone maintenance therapy and require your attention for some other, probably unrelated, health issue. As well, you may see people who are struggling with an opioid addiction and could benefit from enrolling in a methadone program. So here are some things you should know about how methadone maintenance may affect the treatment of other health issues.

At what dose do you prescribe methadone?
The dose range for a single oral administration for pain relief is 5-15 mg. The half-life of the drug is 22-26 hours in most people, but the analgesic half-life is only 6-8 hours. For this reason, once-a-day dosing for pain often provides inadequate control, and the patient may continue to seek alternative opioids to augment the methadone effects or require very high doses of methadone to ensure pain relief. When other opioids are added, there's always a risk of overdose as the patient attempts to self-medicate. In cases where the methadone dosage needs to be high, overdose can be avoided by judicious adjustment of the dose, but high maintenance levels may complicate the management of any future acute pain states.

When used in maintenance programs, the dosage range for methadone is quite variable, but the majority of patients stabilize well between 80 and 120 mg. Most authors consider > 120 mg as high, but dosing in the range of 200 mg isn't uncommon. The optimal dose for a maintenance client is one that blocks withdrawal, cuts cravings for short-acting drugs and creates neither sedation nor euphoria.

Physicians who wish to prescribe or administer methadone in any circumstance must obtain an authorization from the Minister of Health Canada and state the intended use for the drug -- i.e. pain control or dependence maintenance. The authorization is issued upon recommendation by the Provincial College of Physicians and Surgeons of the requesting physician. Different jurisdictions have differing educational requirements for doctors requesting authorization.

What drug interactions should I watch out for?
As methadone is a µ-opioid receptor agonist, it has the same side effect profile as other µ-agonists, but it's less euphorigenic. It also has the same drug-drug interactions. When mixed with other central nervous system depressants -- alcohol, benzodiazepines -- the effects are synergistic for sedation and disability. There's good evidence that high-dose methadone combined with high-dose benzodiazepines may result in an increased incidence of sleep apnea and sudden death. Cocaine use can destabilize someone on a previously stable methadone dose.

Maintenance Therapy
How does it work?
With chronic exposure to opioids, the human body begins to perceive the presence of the drug as normal and its absence as abnormal. By the time most patients present to maintenance programs, they're no longer using to get high, they're using to prevent being ill. Opioid withdrawal is often described as "the worst" case of the flu, magnified. In an otherwise healthy individual, opioid withdrawal isn't life -- threatening and doesn't include seizures, cardiac irregularities or hallucinations. But patients quickly learn that they need their fix to feel "human" -- so the activities of obtaining the drug, using and recovering from the use become a full-time job.

With methadone, we're providing a long-acting, less euphorigenic product that blocks opioid receptors for an extended time and allows the physical symptoms to subside.

Does additional counselling improve outcome?
The literature has clearly found that patients on methadone alone do better than those not on the drug, but equally as clear is the fact that outcomes are optimized if methadone is administered in the context of a multidisciplinary team that emphasizes the value of psychosocial counselling. Methadone acts to stabilize the patient's use; counselling treats the underlying addiction. High-tolerance clinics may accept ongoing unauthorized substance use and not mandate a psychosocial consult whereas other, lower-tolerance programs often require counselling and have limited tolerance for ongoing use. Most programs use random urine drug screens as a means of assessing compliance and stability.

How do you initiate methadone maintenance therapy?
The general trend is to start low, i.e. with 30 mg/day as a single dose, and to increase the dose every 3-4 days until the patient's objective and subjective symptoms of withdrawal have abated. Increasing the dose faster than this may result in an overdose situation. You can usually stabilize the dose within 4-6 weeks of starting the medication. During this period, the patient may continue to use but generally, as the dose of methadone increases, the need to use decreases. Once stable, there should be no way for the casual observer to identify the person on methadone.

There's little or no requirement to increase the dose once someone has arrived at a stable dose (see the table above for exceptions), and people have stayed on fixed doses for long periods of time. Psychologic cravings alone are an insufficient reason to adjust a dose.

What kind of monitoring is necessary?
During the initiation phase, all clients are seen daily by the pharmacist or at the clinic to take their dose under supervision. Once a level dose and psychosocial stability have been achieved (usually after 2-3 months), the patient may earn "take home" doses or "carries." With this option, individuals earn an additional carry for every month of continuing stability -- up to a maximum of 6 take home doses. So with time, they can progress to a scheme where they have one observed dose per week and take the remaining doses home.

The idea behind one observed dose per week is that it provides a means to ensure the patient is taking the medication and hasn't lost any tolerance for the drug. A loss of tolerance indicates that the person may not be taking the entire dose as prescribed and/or that they might be diverting the drug. The frequency of urine drug screening decreases as the patient achieves higher levels of stability, but many clinics have a policy where clients can be contacted with minimal notice and be asked to come in and provide a urine sample.

How do you deal with relapse?
Once the dose is stabilized, the individual can go back to school, work, etc. and is able to reintegrate into society. Since the very nature of addiction is that of a chronic, relapsing disease, however, some slips and missteps are to be expected. Methadone maintenance is a harm reduction strategy, and a relapse to opioid or other unauthorized substances doesn't generally result in immediate discharge. Should use happen, the clinic will step up the availability of counselling sessions, the frequency of doctor visits and the rate of urine drug testing. It'll also back off on or withdraw carry privileges until the client is once again stable. Discharge should be considered a last resort and only if all attempts to assist the patient have failed.

When do you wean a patient off?
Most clinics recommend that a person stay on stable dosing for a minimum of 6-12 months. If they decide that they'd like to come off after this time, and should the timing seem auspicious to all the care providers involved, then doctor and patient will negotiate a slow tapering off, with the patient setting the rate. A growing body of literature suggests, though, that many clients -- if not the majority -- will need to stay on methadone for an indefinite, possibly permanent, period of time. In other words, some people won't be able to successfully discontinue the drug. There should never be any pressure to decrease drug dose, but if a person expresses a strong desire to attempt this, a taper may be initiated very slowly, with a clear understanding that it'll cease if at any point there's a return of cravings or any other sort of destabilization of the patient's psychosocial status.

Can methadone be used during pregnancy?
Methadone is the treatment of choice in opioid-dependent women who are pregnant. Obviously, abstinence is the ideal option for the baby, but if the mom-to-be is unable to abstain, then the structure and support of a methadone program is the next best thing. The biggest risk of opioid use in pregnancy is withdrawal, the stress of which might be sufficient to trigger a spontaneous termination in the first trimester, and premature labour and fetal death in the last. It's not generally recommended to take women off their opioids during pregnancy, but if this becomes necessary, it's safest to do so during the second trimester.

In either case -- taper or maintenance -- the woman is usually stabilized on methadone as an inpatient. If the goal is to taper the drug, this is generally done slowly as an inpatient, in an attempt to minimize withdrawal. If the decision was made to continue methadone maintenance for the duration of the pregnancy, the patient is started on the drug in hospital using a protocol intended to minimize withdrawal, and then she's transferred to an outpatient program. A woman's daily requirement for methadone generally remains stable throughout her pregnancy, although a slight increase in dose may be necessary during the last trimester.

The structure and stability offered by a methadone maintenance clinic helps the expectant mother to comply with other medical appointments, stabilizes her lifestyle, and enhances her nutrition, rest and exercise -- i.e. it optimizes conditions for the baby. As many women will stabilize on the program, they can often take their babies home postpartum, so the newborn doesn't need to be taken into care.

Methadone does cross the placental barrier and some babies will experience withdrawal after birth. While not life-threatening in adults, opioid withdrawal can be life-threatening to infants. If a mom-to-be is on methadone, however, staff are already alert to the risk and the baby will be monitored closely and medicated as necessary.

Transfer of methadone through breast milk is minimal, so breastfeeding isn't contraindicated. As the opioid reaches its peak level in the blood about 2 hours after ingestion, breastfeeding should best be avoided during this period. It's also generally recommended that at 6 months, the baby is either weaned or the mom comes off methadone.

Pain control
How do you treat pain in the methadone-maintained patient?
When a person's substance use is stabilized with the appropriate dose of methadone, they're not covered for pain. The body now perceives this level of methadone as "normal" and any pain receptor activation puts them into an "abnormal" state.

The first line of pain management in this population should be the use of non-pharmacologic means and of non-opioid medications whenever possible. For cases where opioids are indicated, there seem to be two schools of thought as to how pain should be managed in this context.

Some clinicians prefer to try and treat all pain just using methadone. In this approach, in response to an acute pain situation, the methadone dose would be minimally increased (often 10 mg), and then divided up to be given twice daily for the duration of the pain. The advantage is that you don't have to reintroduce a drug with which the patient has had a problem in the past. On the downside, the person is now on a higher baseline dose, and it's often difficult to get the dose back down.

The second -- and more popular -- approach is to maintain the methadone at baseline, then manage the pain as if the patient weren't on any opiate, using long-acting/delayed-release and less euphorigenic products where feasible. The duration of treatment should be kept as short as possible, and by all means try to avoid the individual's "drug of choice." It's important to remember that this population generally requires somewhat higher-than-typical doses and shorter dosing intervals. This course of action offers good pain control without disrupting the baseline maintenance dose.

What about methadone for chronic pain?
Methadone is a synthetic opioid analgesic with excellent oral bioavailability, a side effect profile similar to other opioid analgesics and a duration of action of at least 8 hours. It can therefore be useful in the management of chronic non-malignant pain. In practice, methadone is a far more potent analgesic than has been suggested by equianalgesic tables, which are based on singledose studies. With repetitive dosing, methadone is approximately 10 times stronger than indicated in these standard tables. The main reason for this is probably the long half-life in the body (24-36 hours), which -- through accumulation -- leads to much higher drug levels than could be predicted from single-dose studies. Methadone takes 5-7 days to reach a steady state at any particular dose. Therefore, when initiating methadone for chronic pain, the physician must be particularly vigilant for undesirable side effects.