- By Sarz Maxwell MD
& Marc Shinderman MD
- Center for Addictive Problems
- 609 N Wells
- Chicago IL 60610
-
- Abstract
Using signs, symptoms and serum
methadone levels to guide evaluation, we treated 188 patients in a methadone
maintenance program with doses of methadone exceeding 100 mg/d.
The mean dose of these higher dose (HD) patients was 206 mg/d (range
110-780 mg/d). A comparison group
was randomly selected from the general clinic population (mean dose 69mg/d).
At intake the HD group reported $136/day of heroin use vs $88/day in the
C group. The HD group had more
patients whose opiate of choice was an oral pharmaceutical (27% versus 2% of the
C group). Fifty-eight percent of
the HD group had comorbid psychiatric diagnoses compared to 33% of the C group.
Response to psychopharmacologic treatment was enhanced by increased
methadone dose in HD patients with refractory psychiatric disorders.
Urine toxicologies described as before were collected prior to
increase over 100mg/d in the HD group or at the first routine urine toxicology
collection of the calendar year for the C group.
These results were compared to the most recent urine toxicologies for
both groups (after). The
percentage of toxicologies positive for illicit drugs in the HD group dropped
from 91% before to 9% after. The
C group were 52% positive before and 30% positive after. We conclude that doses of methadone in excess of 100mg/d
(range 110-780 mg/d in our sample of 188 patients) are not only safe but
necessary to prevent illicit opiate use, stabilize psychiatric symptoms, and
diminish abuse of alcohol and benzodiazepines in many patients.
Introduction
Methadone has been
used since the middle 1960s for the treatment of opiate addiction. Methadone
maintenance treatment (MMT) decreases illicit opiate use (Dole, Nyswander &
Kreek 1966) and reduces the incidence of many associated factors, including
crime (Senay 1985), unemployment (Martin, Payte & Zweben 1991),
and HIV infection (Barthwell & Senay 1989).
In 1966 Dole , Nyswander & Kreek recommended a dose of 80 – 120
mg/day of methadone. In the
1980s, many MMT programs attempted to minimize methadone dose (Craig 1980).
Some used punitive
interventions such as reducing methadone dose in response to illicit opiate use
(Iguchi et al 1988). Many MMT
clinics prescribed increased psychosocial interventions instead of increased
medication dose for patients who continued to abuse opiates.
Some practitioners, however, continued to view MMT as medical treatment.
Clinical utilization of serum methadone levels began in the 1980s, and
became more widespread in the 1990s (Bell et al 1988; Chang et al 1991; Kell
1995; Loimer & Schmid 1992; Tennant 1987; Tennant et al 1984).
Though several researchers have attempted to maintain patients at serum
methadone levels as low as 100 ng/ml (Bell et al 1988), it is now generally
agreed that 400 ng/ml is the lowest serum methadone level that can reliably
support effective methadone maintenance therapy (CSAT-TIP 1993).
METHODS
The Center for
Addictive Problems (CAP) is a fee-for-service MMT program (MMTP) with two clinic
locations. The mean daily dose of methadone for the clinic population of 1220 at
the time of data collection was 78 mg/day. Clinic I is located in Chicago, in continuous operation since
1977, with an active census of approximately 1,100 patients.
Clinic II is a suburban location under CAP management since 12/96, with a
census of approximately 120. The
188 patients treated with doses of methadone >100mg/d were drawn from both
clinics: 157 from Clinic I and 31 from Clinic II.
Patients who were identified as being clinically unstable despite
methadone treatment at 100 mg/d were referred by nursing or counseling staff for
medical evaluation. Serum methadone levels were measured while the patient was
taking 100-120 mg/d and, in some patients, repeated as patients passed
successive 100 mg intervals. Blood
was drawn onsite 22-26 hours after an observed dose of methadone.
Methadone serum concentration determinations were performed by Quest and
Smith Kline Beecham Laboratories in San Diego, CA.
There was no standard protocol for dose titration: patients methadone
doses were individually titrated against signs and symptoms of opiate
withdrawal. The charts of these 188
patients were reviewed and the data compared with data from the charts of 102
patients randomly selected from the general population at Clinic I.
Urine toxicologies
from 1-4 weeks prior to increase of dose over 100mg/d for the 188 patients
requiring higher doses of methadone (HD) were compared to the first urine
toxicology of the calendar year 1996 for the comparison group .
We identify these results as the before sample.
The time between the before and after urine toxicologies for
the C group ranged from 3 to 6 months. We used this 3-to-6-month time span to
compare urine toxicologies because it was similar to the time span necessary for
titration from 100mg to final dose in the HD group. The after sample for both groups refers to the most
recent urine toxicology available at the time of data collection.
Urine toxicologies were reported as positive if they showed any illicit
drug. Urine toxicologies do not
reflect use of illicitly obtained methadone, but
patients who reported regular use of illicit methadone were reported as
having a positive toxicology. Patients
in both groups were reported as having concomitant psychiatric illness if they
were taking psychotropic medication, including antidepressants, anxiolytics,
mood stabilizers, and antipsychotics. In
most cases these medications were being prescribed by our clinics
psychiatrists.
RESULTS
The HD population of
188 patients included 122 males and 66 females. The majority of HD patients (84%, n=157) were attending
Clinic I; 31 patients (16%) were
from Clinic II. All 102 (66 male,
36 female) patients in the control group were attending Clinic I.
Mean methadone dose for the HD patients was 206 mg/d (range 120 – 780),
patients had been in MMT an average of 117 weeks (range 1-844) before taking a
dose exceeding 100mg/d, and patients had been taking a dose exceeding 100mg for
an average of 31 weeks (range 3-346). Mean
methadone dose in the C group was 69 mg/d, (range 10-100), and average time in
treatment was 252 weeks (range 1-856).
Fifty-eight percent
of the HD group (n=109) were taking psychotropic medications.
These included selective serotonin reuptake inhibitor antidepressants
(53%, n=58), benzodiazepines (49%,
n=54), tricyclic antidepressants (32%, n=35), divalproex (19%, n=21),
methylphenidate (5%, n=5), neuroleptics (2%, n=2) and lithium (2%, n=2).
About half of the patients taking psychotropics (49%, n=54) were taking
more than one medication. An exact
breakdown of diagnoses was not possible, but the majority of patients suffered
from affective disorders (predominantly major depression) and anxiety disorders
(predominantly post-traumatic stress and panic disorders).
The proportion of C patients taking psychotropic medications was less
(35%, n=36) but the breakdown of diagnoses and medications were similar:
53% (n=19) taking selective serotonin reuptake inhibitor antidepressants;
36% (n=13) tricyclic antidepressants; 33% (n=12) prescribed benzodiazepines; 17%
(n=6) taking divalproex; 6% (n=2) antipsychotic medications and 3% (n=1)
prescribed methylphenidate. The HD
group reported greater amounts of heroin use at intake:
average $136/day (range $40 – 800) compared to $88/d (range $30-200) in
the C group. Route of heroin
administration was similar for the two groups.
Among the HD patients 51% (n=82) were IVDU and 32% (n=51) used heroin by
nasal insufflation. The comparative
figures for the C group were 64% (n=65) and 33% (n=34), respectively.
In both groups there were a number (5% of C, 14% of HD) who had been in
MMT continuously for more than 15 years. These
patients were not included in computing heroin habit.
There was a difference between groups in number of patients who
preferentially used prescription opiates: 2%
(n=2) of the C group as compared to 27% (n=50) of the HD group.
Urine toxicology
results for the C group were 51% (n=52) positive/before and 30% (n=31)
positive/after. For the HD group,
urine toxicologies were positive for 82% (n=155) before high dose, and 9% (n=17)
after. When the 17 HD patients who
were positive/after were compared to those who were negative/after, the
positive/after patients tended to
have a lower average dose (143 mg vs 213mg), and less time in treatment at
>100mg/d (13 weeks vs 33 weeks). The
positive/after patients were more likely to be in treatment at Clinic II:
seven of 31 Clinic II patients (44%) were positive/after, compared to 10
of 157 Clinic II patients (6%).
Termination rates and
patterns for the entire population at Clinic I during the period studied were
obtained. Therapeutic termination was defined as one which followed planned,
medically-monitored withdrawal procedures.
Non-therapeutic termination describes abrupt discontinuation of treatment
without notice or administrative withdrawal of medication because of
noncompliance with clinic regulations. The
overall 12-month termination rate for the entire clinic was 65%. The majority of
these (70%) were non-therapeutic. Transfer
to other MMTPs accounted for 10%, therapeutic withdrawal 8%, death 2% and
incarceration 1% of the terminations in the general Clinic I population.
Among the 188 HD patients, there have been only 23 terminations, for a
12-month termination rate of 12%. Again,
the majority of terminations were non-therapeutic (78%), with two therapeutic
terminations and one each incarceration, death, and transfer.
DISCUSSION
In the 1980s,
practitioners were under a great deal of pressure to apply restrictive and
punitive measures to addiction treatment. In
MMT programs, contingency dosing and very low ceiling doses were attempted and
shown to be of suboptimal efficacy. Numerous studies concluded that urine toxicology results
positve for illicit opiates show robust inverse correlation to methadone dose (Hartel
et al 1995; Siassi, Angle & Alston 1977; Strain et al 1993).
In our sample 30% of patients in the control group had positive urine
toxicologies in the after sampling. This
is consistent with the rate of illicit drug use in MMTPs nationwide (US-GAO
1990). We identified a group of
patients who, despite doses up to 100mg/day, had a very high rate of illicit
opiate use (82%). When these patients were individually titrated to doses of
methadone that resulted in no objective signs or subjective symptoms of
withdrawal, the percentage of patients with positive urine toxicologies dropped
to 9% (see Figure 1).
This rate of illicit drug use is several orders of magnitude lower than
most clinics achieve (US-GAO 1990).
Another common
outcome measure for MMT is retention in treatment.
Nationally, the six-month retention rate averages 54% (US-GAO 1990).
There is a clear correlation between increased methadone dose and
increased retention in treatment (Capelhorn & Bell 1991).
This association of methadone dose with retention in treatment is
strongly illustrated in our sample of HD patients, 84% of whom were retained in
treatment for a year or more. In
this age of HIV-spectrum disease, retention in treatment is a primary treatment
goal. Discharging patients because
of illicit opiate use can not be justified.
All patients at CAP
are educated about the need for adequate doses of methadone to eliminate illicit
drug use and craving. Patients with
consistently positive urine toxicologies are referred for medical evaluation by
nursing and/or counseling staff. The patient is evaluated for signs and symptoms
of opiate abstinence syndrome (OAS), and dose adjustments are made accordingly.
As these dosing practices developed and became known throughout the clinic
population, more patients became willing to spontaneously report illicit drug
use, including use of illicit methadone. Unsurprisingly,
patients were more likely to report illicit use when they were given appropriate
treatment rather than punishment for their candor.
When we first started
treating patients with doses exceeding 100mg/d we were aware that we were
prescribing differently than most programs in the US. Consequently we performed serum methadone levels (SMLs) often
for the first year, and our clinical experience during this time was consistent
with the empirical findings of Hiltunen et al (1995). Our conclusions are more clinical than empirical, as we did
not do serial SMLs for the majority of HD patients, and we did no SMLs for
comparison purposes in the C group. Our
clinical findings are illustrated in Figure 2.
When the serum
methadone level (SML) is very low (<200ng/ml), most patients exhibit the
familiar objective signs of OAS: mydriasis,
rhinorrhea, piloerection, arthralgia, and nausea/ vomiting/ diarrhea.
As the dose of methadone is increased and the SML rises above 200ng/ml,
these objective criteria for OAS
disappear. This may be one reason for reports that 100-150 ng/ml was an
adequate SML (Bell et al 1988). However,
patients may continue to experience dysphoria, insomnia, anxiety, and craving.
Further increases in methadone dose alleviate these subjective symptoms.
We found SML very helpful in confirming inadequate dose, but less helpful
in determining adequate dose. Although
400 ng/dl is the lowest SML that is usually effective, some HD patients had SMLs
of 800 -1200ng/ml when titrated to doses resulting in no signs of intoxication,
no symptoms of withdrawal, and no illicit substance use.
These
higher-than-anticipated SML results may be due to differential effects and
metabolism of d- & l- enantiomers (stereoisomers) of methadone (Olsen et al
1977). Recent European work
examining inter-individual response to dose in methadone-dependent patients
describes the l-enantiomer as 50 times more biologically active than the d-
enantiomer (Eap et al 1998). Methadone
products in the US are racemic (1:1 ratio of l:d enantiomers) but standard tests
for serum methadone levels report the sum of both enantiomers (l+d). Eaps
group measured serum levels of the l- and d- forms separately. They found seven-fold inter-individual variability in the
ratio of the enantiomers in the serum of different patients on equivalent doses.
Eap attributes 47% of the variability to heritable cytochrome P450
mechanisms.
Thus an adequate, or
even toxic, SML may be reported for a patient whose serum level of active l-
enantiomer is inadequate for maintenance. Clinically,
this occurs in patients whose l:d methadone ratios are 0.65 or less (Ortelli et al 1997).
Other patients may have l:d ratios much greater than 1, and will be
clinically stable (no signs or symptoms of OAS, no illicit drug use) with SMLs
well below 400 ng/ml. Therefore, relying on a standard SML alone to determine
adequate methadone dosage will result in dosing errors in both directions for a
significant percentage of patients.
Currently, testing
for serum l:d enantiomer ratios is relatively costly. Medical evaluation of objective signs and subjective symptoms
is a sensitive, reliable, and cost-effective method of dose titration.
Using these clinical indicators to determine adequate methadone dose
results in dramatic inter-individual variability in methadone dose.
Our original expectation was that some patients would seek intoxicating
doses of medication. This
concern was rapidly dispelled. Not
one patient continued to ask for increases in methadone dose after reaching
clinical stabilization. In fact,
many patients were reluctant to accept the increases that we recommended, and
required support and reassurance to achieve an adequate dose.
We have learned that
continued use of illicit opiates is the best indication for increasing methadone
dose, and supersedes standard SML
results. For 53 (28%) of the
HD group no SML determinations were performed.
For many patients (n=95; 53%) SML
was not repeated after the initial determination at 100-120mg/d.
We have become confident using the same criteria for high-dose titration
as we have always used for routine dose titration:
signs and symptoms of OAS.
The United States
GAOs findings about continued illicit drug use in MMT patients (US-GAO)
support our finding that, when allowed to set their own dose of methadone,
patients tend to maintain themselves at subtherapeutic doses.
Significant numbers of patients continue to use illicit drugs while
saying I dont want to go too high on the methadone.
MMTPs may discourage adequate methadone dose by imposing arbitrary dose
ceilings and/or restricting privileges based on dose, communicating prejudices
regarding dosage, and supporting negative myths about methadone.
Additionally, the disinclination to take any medication as prescribed is
at least as prevalent in methadone-maintained heroin addicts as in patients with
other chronic diseases, such as diabetes, schizophrenia, depression, and
hypertension. Methadone is
different from the medications used for those illnesses; it is a medication
encumbered with overwhelming stigma and significant practical barriers to
compliance. MMT patients need even
more support and education for adequate pharmacological maintenance than do
patients with other chronic disorders.
Measurement of SML is
very useful as an educational tool to encourage a fearful patient to accept an
adequate dose or to assure a less experienced colleague that a dose increase is
justified. We also measure SML when clinical signs and symptoms are unclear or
conflicting. However, we rely more
heavily upon objective signs such as continued substance abuse and signs of OAS.
We have also learned to take patients subjective complaints of
distress very seriously. We have confirmed that patients reports of
subjective symptoms are usually reliable,
and are a more appropriate criterion for dose titration than costly, invasive,
time-consuming, and (as described above) sometimes unreliable SML.
Using these guidelines we have been
able to bring levels of illicit drug use in this high-risk population to
unprecedented lows.
We report seventeen
HD patients whose urine toxicology results were positive for illicit drug use in
the after time frame (positive/after), and can compare these 17 patients
to the 169 patients who were negative/after.
The positive/after patients had lower average dose of methadone (143mg
vs. 213mg) and had been on doses exceeding 100mg/d for a shorter time (13 weeks
vs 33 weeks). Because this study is
naturalistic, we infer that these 17 patients are still in the process of dose
titration and have not yet achieved an adequate stabilizing dose.
Seven of 31 Clinic II patients (44%) were positive/after, compared to 10
of 157 Clinic I patients (6%). This
supports the medical conceptualization of methadone treatment.
Clinic I with over 1100 patients has doctor appointments available 6 days
a week, while Clinic II has doctors available only once a week. Clinic II patients were identified and referred for medical
evaluation more slowly and their dose adjustments made less frequently compared
to patients at the clinic with more access to a physician.
We conclude that physician contact has a positive effect on treatment
outcome. Addictions treatment has
been largely a non-medical specialty. We
suggest that increased clinical involvement of addictions medicine specialists
improves treatment outcome.
We found a higher
incidence of psychiatric diagnoses in the HD group (58%) than in the C group
(35%) (See Figure 3). This
difference may be an artifact, as patients in the HD group had more physician
contact than those in the C group. Physician
contact was required for a dose increase over 100mg/d and for subsequent
increases. Probability of
recognizing a psychiatric disorder was therefore increased.
The 58% incidence in our HD sample is consistent with epidemiological
studies of psychopathology in addicted patients (Abbott, Weller & Walker
1994; Jacobs, Doft & Koger 1981;
Milby et al 1996;
Nunes et al 1994).
It is possible that
there is a correlation between Axis I psychopathology and high methadone dose
requirement. Such a correlation has
been reported by Maremmani (1997). This
study found that a significantly higher mean dose of methadone was required to
stabilize patients with psychotic, bipolar, depressive disorders and alcohol
abuse disorders than that required by patients with heroin dependence alone.
Whether causally-related or not, the juxtaposition of psychiatric
disorder and higher dosage requirement allowed us to make some interesting
observations regarding clinical management of these dually-diagnosed patients.
The use of opiate agonists as psychotropic agents is not new. Methadone has established psychotropic efficacy (Musselman
& Kell 1995). We observed a
subset of patients whose chronic depressive disorders had been refractory for
years to many varied and heroic antidepressant regimens. When these patients methadone doses were titrated against
their depressive symptoms, antidepressant efficacy was achieved.
In some cases antidepressant medications were able to be decreased or
discontinued and in all cases the efficacy of the antidepressants was greatly
enhanced. It reminded us that
methadone is a powerful psychotropic tool, and we now use methadone more
aggressively in the treatment of psychiatric symptoms.
In several patients, dysphoria and anxiety were the sole subjective
symptoms against which we titrated the last 10-15% of methadone dose. These
phenomena certainly deserve further study.
Our clinical
experiences with benzodiazepine abuse also bear mention.
Others have reported that methadone-maintained patients use
benzodiazepines to enhance methadone effects (Preston et al 1984).
We now treat abuse of benzodiazepines in MMT patients as a symptom of
inadequate methadone dose. Titration
of methadone dose against use of benzodiazepines has been very useful in
minimizing or eliminating abuse of benzodiazepines in motivated patients. The physician initiates the cooperative process by
prescribing benzodiazepines ad libitum as long as the patient agrees to upward
titration of the methadone dose. The
patients benzodiazepine requirement (licit and illicit) is converated to a
single long-acting benzodiazepine, administered and monitored by medical staff.
We have been able to eliminate inappropriate use of benzodiazepines in
many patients. Our experience with
alcohol abuse is similar to that with benzodiazepines.
Most alcohol-abusing patients find that increased methadone dose helps to
curb alcohol cravings. In these
patients we titrate methadone dose against the patients report of alcohol
cravings, though dose titration may be complicated by acute alcohol
intoxication. Our clinic policy is
to withhold methadone if the breathalyzer Reading exceeds 0.05.
The efficacy of opiate substitution in relieving alcohol cravings is not
surprising, as the opioidergic mechanism of alcohols action is well known
(Sinclair, Adkins & Walker 1973), and naltrexone, an opiate antagonist, is
effective in the treatment of alcohol use disorders. (OMalley et al 1996;
OBrien, Volpicelli & Volpicelli 1996).
Cocaine is more
problematic. The literature
provides conflicting reports regarding opiate agonist efficacy in the treatment
of cocaine abuse (Preston et al 1996; Rawson et al 1994; Tennant & Shannon
1995). Although we do not have the
data to conclude that methadone is an efficacious treatment for cocaine abuse,
we can report our clinical experience. In patients with primary opiate
dependence and secondary cocaine use, aggressive methadone titration combined
with antidepressant therapy can be helpful for motivated patients.
Zubieta et al (1996) reported upregulation of mu receptor binding in
response to cocaine bingeing. This
has two implications for the methadone-maintained patient.
First, it is evidence for opioidergic involvement in cocaine dependence
and craving. Secondly, it helps us
understand the increased methadone requirement seen in patients who are using
cocaine. This elevated methadone
dose requirement must be met by appropriate increases in methadone dose.
Retention in treatment is crucial to achieve any long term improvement
and retention in treatment is dependent upon adequate methadone dose.
The concept of opioid
addiction as a metabolic disease involving deficiency of endogenous ligand is
not new. It was first suggested in
1966 in Dole, Nyswander, & Kreeks original article, and has subsequently
been discussed by many authors (Martin, Payte & Zweben 1991;
Goldstein 1991; Kreek 1992). Most
patients on an adequate dose of methadone can achieve a pharmacologic
approximation of the normal or healthy neurophysiologic state.
If the dose of methadone is inadequate, illicit supplementation will be
necessary to approximate healthy neurophysiology (See Figure 4).
In conclusion, we found that the dose of methadone necessary for
effective pharmacologic treatment of opiate addiction has wider inter-individual
variability than has been generally acknowledged in most treatment settings.
Patients treated with inadequate doses of methadone commonly supplement
their dose with illicit opiates, benzodiazepines, and alcohol.
Treatment response can be maximized by increasing the dose of methadone
in response to patient reports of illicit drug use and subjective distress.
Patients do not request inappropriate increases of methadone.
We have yet to encounter patients whose illicit opiate use can not be
eliminated by titrating methadone against symptoms of OAS and signs of drug
abuse.
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Thanks To The Center For
Addictive Problems for this invaluable study.
