Addiction (1996) 91(11), 1699-1704

RESEARCH REPORT

Non-prescribed drug use during methadonetreatment by clinic- and community-basedpatients

KIM WOLFF,' ALASTAIR W. M. HAY/ ANDREW VAIL,' KEVINHARRISON^ & DUNCAN RAISTRICK*

'Division of Pathology and Institute of Epidemiology, Research School of Medicine,The University of Leeds, ^Department of Chemical Pathology, Leeds General Infirmaiy &^Leeds Addiction Unit, Leeds, UK

AbstractWe investigated the efficacy of methadone maintenance treatment in clinic-based (n= 10) and community-based (n= 10) patients by studying the relationships between dose, plasma concentrations of methadone andnon-prescribed drug-use using logistic regression. We found that chnic-based patients had significantly reducedodds of having a urine sample test positive for illicit drugs when compared to community-based patients(OR = 0.20; 95% confidence interval 0.10-0.38: p< 0.001). There was no relationship between eithermethadone dose or plasma methadone concentration and testing positive for non-prescribed drugs (includingcocaine, cannabis, amphetamine, ecstasy, benzodiazepines). We looked specifically at the misuse cf opiatedrugs. Location wets again important and clinic-based patients had significantly reduced odds of having aurine sample test positive for opiate drugs (OR= 0.36, 95% confidence interval 0.13-0.71: p'^0.004).Opiate drug use in our patients was also significantly related to plasma methadone concentration, increasingnoticeably when the drug concentration <0.48 nmol/L (p^0.04). We found no relationship betweenmethadone dose and odds of having a positive urine drug test in either dinic- or community-based patients.

Introduction The Leeds Addiction Unit randomly screensRegular analysis of urine samples from subjects urine samples from all patients prescribedaddicted to opiate drugs and prescribed metha- methadone. Data collected between 1987 anddone for treatment is valuable for the manage- 1995 showed that during extended methadonement of patients. Screening for the presence of prescribing (maintenance) patients used a widedrugs of misuse helps in four ways: it assists variety of non-prescribed substances, includingdiagnosis; enables treatment to be supervised cocaine, sympathomimedc amines, catinabis,more carefully; permits identification of particu- opiates and amphetamines.' The misuse of otherlar patterns of misuse; and, perhaps most impor- drugs during methadone maintenance treatmenttantly, provides a focus for patient/therapist is a significant problem, particularly the use ofdiscussion of progress. several unrelated drugs at one time (polydrug

Correspondence to: Kim Wolff, Division of Pathology and Institute of Epidemiology, Research School ofMedicine, The University of Leeds, Old Medical School, Leeds, LS2 9JT, UK. Fax: 0113 233 5672.

0965-2140/96/111699-06 $8.00 © Society for the Study of Addiction to Alcohol and Other Drugs

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1700 Kim Wolff et al.

use). Polydrug use is a well-known practiceamong UK addicts,^"' but there are few data onit during long-term methadone treatment.

Research on drug misuse during methadonetreatment has concentrated on the relationshipbetween methadone dose and extent of illicitheroin use. Studies in the United States reponthat high doses (70-100 mg methadone/day) areeffective in eliminating the desire for heroin;*''however, others have suggested that provided anindividual's dependence upon opioid drugs islow, a small dose of methadone is just as effec-tive.*'' Very few studies have investigated pa-dents maintained on < 60 mg/methadone a day,and particularly the relationship between non-prescribed drug use and the more immediatelyrelevant variable, plasma methadone concen-tration.^"

We decided, therefore, to investigate patientson different fixed doses during methadonemaintenance to assess the extent of non-pre-scribed drug use (other than methadone) and itsrelationship with plasma methadone concentra-tions.

Materials and methodsSubjects and study protocolApproval was obtained from the local ResearchEthics Committee before the study commenced.Twenty-nine patients anending the Leeds Ad-diction Unit for treatment were randomly re-cruited onto the study, as non-paid volunteers.Nine patients defaulted, leaving before treatmentwas complete and before sufScient laboratorydata could be collected.

The subjects were representative of two differ-ent patient types: clinic-based patients I-IO, aged23-34 years (median 26.5, interquartile range25-29 years) who attended the clinic on a dailybasis and were administered their prescription onsite, and community-based patients 11—20, aged26-60 years (median 33, interquartile range 29-33 years) who collected their prescription from apharmacy and had less frequent contact with theunit.

Clinic-based patients had been prescribedmethadone for periods from 0.8 to 24 months(median 3, interquartile range 0.8—12 months)and community-based for 1-60 months (median18, interquartile range 1-27 months) before thestudy began. All patients were informed of thepurpose of the study and gave their consent toblood and urine sampling.

Patients' samplesBlood (10 mL), drawn by venepuncture intohepadnized Monovette collection tubes (Sare-ston Ltd, Leicester, UK) and urine (20 mL)samples were collected before the consumptionof the daily methadone dose. Before screeningurine samples for non-prescribed drugs patientswere interviewed and given the opportunity tovolunteer information about non-prescribeddrug consumption. Samples were collectedweekly, once every two weeks, or monthly.

Liquid chromatographyHPLC was performed with a model 501 HPLCsolvent-delivery system [Millipore (UK Ltd, Wa-ters Chromatography Div., Harrow, Middlesex,HAl 2YH, UK] and a Model 231/401 Gilsonautosampler (Anachem UK Ltd, Luton, Bed-fordshire, UK), fitted with a 50-/jL loop. Toanalyse plasma samples for methadone we usedan Apex-1 silica column, 25 cm X 0.46 (i.d.),packed with 5-^m-diameter particles (JonesChromatography, Llambradach, Mid Glamor-gan, UK) and a mobile phase (recycling at 2mL/min) consisting of methanol/1, 2-dichloroethane/isopropanol/aqueous (100 g/L)ammonium perchlorate (90.5/5/4/0.5 by vol).Methadone and benzhexol (internal standard)were detected at 215 nm with a Model 455 LCspectrophotcmeter coupled to a Model 747data-module integrator (both from Waters Chro-matography Div.)."

Thin layer chromatography (TLC)TLC was performed using two Desaga Horizon-tal TLC chambers (Laserchrom Analytical,Gravesend, UK), one containing Solvent A(ethylacetate/isopropanol/methanol/8 M ammo-niimi hydroxide; 8/1.5/0.3/0.8 by vol) and other,solvent B (1,2-dichloroethane/isopropanol/meth-anol/8 M ammonium hydroxide; 2/2/2/0.7 byvol). Analytical plates (5X5 cm) prepared frompre-washed 20 X 20 cm silica gel plates (What-man 60A/UV254, polyester-backed LaserchromAnalytical) were used for the analysis. Migrationof the solvent (A or B) to the top of the platetook 8-10 minutes. Plates were dried in an ovenat 110°C for 2 minutes and then sprayed foridentification with iodoplatinate solution fol-lowed by 5% sulphuric acid.'^

Drug use during methadone treatment 1701

Table 1. Clmk-based patient characteristics

Patient

Dose (mg/day)Mean plasma

methadone (nmol)Total urines testedUrines positive

for illicit drugsUrines positive

for opiate drugs

1

35

0.236

0

0

2

35

0.3915

0

0

3

60

1.2314

6

6

4

40

0.4213

3

1

5

20

0.2317

13

10

6

35

0.4515

3

3

7

50

0.2314

12

12

8

60

0.9727

0

0

9

40

0.297

2

0

10

36

0.239

0

0

ResultsAssay validationWithin-rvm and between-run assay reproducibil-ity of methadone measurements were assessed(M = 10 each) and the means (nmol/L) andcoefficients of variation (CV%) were 0.2, SD0.006 (3.2%) and 0.2, SD 0.029 (9.8%), re-spectively." The in-house TLC method readilydetected drugs and metabolites in urine at 0.05-1 mg^.'^ TTie EMIT cut-ofif value for screeningwas 0.3 mg/L for opiates, methadone, benzodi-azepines (as oxazepam) and benzoylecgonine;0.1 mg/L for cannabinoids, and 1 mg/L for am-phetamines.

StatisticsLogistic regression analysis was used to examinewhether methadone dose, treatment location(clinic or community) and plasma methadoneconcentration were related to concomitant non-prescdbed drug use and in particular illicit opiateuse.

Clinical resultsWe found that there was a significant differencebetween the clinic-based (numbers 1-10) andthe community-based (numbers 11-20) patientswith regard to drug misuse during treatment.Patietits attending the addiction unit (clinic) ona daily basis had significantly reduced odds ofhaving urine samples test positive for non-pre-scribed drugs (OR =0.20; 95% CI 0.10-0.38:p<0.001). The community-based group tendedto use illicit drugs more frequently than thosepatients based at the addiction unit: the medianpercentage of urine samples positive for drugs ofabuse being 26% (interquartile range 0-43%) forthe clinic-based and 42% (interquartile range

0-72%) for the community-based patients, re-spectively (Tables 1 and 2). We found the samewas true when we looked at the incidence ofopiate drug use during methadone treatment i.e.the clinic-based group had significantly reducedodds of having a urine sample test positive foropiate drugs (OR = 0.36, 95% CI 0.18-0.71:p = 0.004).

We also studied the relationship betweenplasma methadone concentration and non-pre-scribed drug use for both clinic- and commimity-based (n = 20) patients under steady-stateconditions dudng loi^-term methadone mainte-nance; we found no relationship between plasmamethadone concentration and the chance ofhaving a urine sample test positive for non-prescribed drugs. However, as can be seen inFig. 1, there was a significant relationship be-tween opiate drug use and plasma methadoneconcentration (p = 0.04). Some drug misuse wasapparent at virtually every plasma methadoneconcentration but was significantly more numer-ous when the concentration was lower.

Finally, we looked at the relationship betweendaily methadone dose and illicit drug use. Usinglogistic regression we found no relationship be-tween methadone dose and the incidence of non-prescribed (p = 0.6) and in particular opiate(p = 0.95) drug use. Some misuse of drugs wasapparent over a wide range of methadone dosesup to and including those receiving 60 mgmethadone per day. However, no illicit drugswere used by those prescribed 80 mg or 100 mgmethadone per day.

DiscussionOur study clearly shows that location is veryimportant in relation to the extent of non-prescribed drug use. We found that clinic-based

1702 Kim Wolff etai.

Table 2. Community-based patient characteristics

Patient

Dose (mg/day)Mean plasma

methadone (nmol)Total iirines testedUrines positive

for illicit drugsUrines positive

for opiate drugs

11

50

1.6213

7

2

12

60

0.977

2

2

13

55

0.9014

14

1

14

20

0.237

0

0

15

60

0.717

7

7

16

60

0.9415

10

5

17

21

0.399

8

8

18

30

0.457

0

0

19

36

0.7614

12

10

20

100

1.587

0

0

patients (who colleaed their methadone on adaily basis from the addiction unit) had asignificantly reduced chance of having a urinesample test positive for non-prescribed drugs ingeneral (p< 0.001) or opiate drugs in particular(p~ 0.004) than patients who coUerted theirmethadone less firequently from a pharmacy.

The definition of an adequate and appropriatemethadone dose is one that prevents the onset ofopiate withdrawal symptoms for a minimum of24 hours; eliminates craving for heroin-Ukedrugs; and prevents the euphoric effects of non-prescribed opiates."''"' To achieve this state it isnecessary to continuously saturate the opioid^-receptors in the body by maintaining the con-centration of methadone in plasma above a cer-tain critical level.'" Some of our subjects wouldseem to have achieved this given that they had

no need to resort to non-prescribed opiate drugs,but the situation is clearly complex (Tables 1and 2).

It appeared from our study that a threshold forthe concentration of methadone in plasma (ap-proximately 0.50 nmol/L) might exist belowwhich supplementation with non-prescribed opi-ates is more cotnmon. It may be that /j-receptoractivity cannot be sustained over the 24-hourperiod at very low plasma levels in drug depen-dent individuals. Similar findings were reportedby Dole," and Holmstrand," who found thatthe best record of rehabilitation was obtained insubjects discharged with steady-state plasmamethadone concentrations above 0.65 nmol/L.

Data describing the relationship betweenplasma methadone concentration and patterns ofnon-prescribed drug use has not been reponed

1.00CO

"Q.

° 0.75

II 0.50

o

I 0.25

8 •0.2 0;4 0.6 0.8 1.0 1,2 1.4

Plasma methadone concentration {nmol)1,6 1.8

Figure 1. Relationship between mean steady-statt plasma methadone concentration and proportion of urine samples positivefor opioid drugs in clinic-based (t) and community-based (O) patients. 3 = Three patients (two clitac- and onecommunity-based) had a mean plasma methadone concentration of 0.2 nmol and did net have opiate drugs detected in any

of their urine samples. -F w = urine positive for opiate drug(s).

Drug ttse during methadone treatment 1703

previously in patients prescribed the wide rangeof doses (20-100 mg/methadone per day; 0.26-1.33 mg/kg/day) used by our subjects. Dose inour patients was not related to the extent ofnon-prescribed drug-use. For those patients ofours who did not misuse drugs the daily dose ofmethadone was wide ranging, from 20 to 100mg. "nUs may have been because in some, psy-chological factors, particularly the wish for anopiate effect, overtook the pharmacological fac-tors. Consequently, the patient who is not awareof the need for a change in life-style ("pre-contemplater") and who is receiving methadonefor harm reduction purposes will take a muchhigher dose than the patient who has substancemisuse under control ("action-stage") and wantsto leave the drug scene.'*

Early reports in the United States indicate thatthe most favourable outcome of methadonetreatment (usually a reduction in heroin use) isassociated with high doses, > 80 mg methadoneper day." The recommended dose for long-termmaintenance treatment in the United States isbetween 60 mg and 100 mg of methadone aday,'* the former said to be the lowest effectivemaintenance dose." In Britain the appropriatedosage of methadone has recently been recom-mended as 50-120 mg per day.̂ " Doses <40mg methadone a day are considered by some tobe inappropriate for methadone maintenancetreatment.^' Britain and the United States, how-ever, have very different treatment services andmethadone delivery systems. This probably ex-plains the differences in the reports of how par-ticular doses of methadone affect the outcome oftreatment.''̂ ^"^* It is difficult to compare non-prescribed drug use in patients prescribed highor low dose methadone because doses of > 100mg methadone a day are not common in Britain.In the final analysis however, the relationshipbetween methadone dose and illicit opiate use isnot at all clear-cut.^'

Our data suggest that when the plasma metha-done concentration was lower patients weremore likely to abuse non-prescribed opiates thanother classes of drugs. It has been suggested thatadequate plasma concentrations of methadonesuppressed the abuse, not only of heroin, but ofnon-opiate drugs such as alcohol and benzodi-azepines.^' For our patients there was norelationship between the misuse of am-phetamine-type drugs, cocaine and cannabis,and either the dose of methadone or the plasma

methadone concentration. This phenomenonhas been observed previously.^'

Bell et al.^ recently reported that the regular,or episodic use of benzodiazepines, alcohol andstimulants by methadone maintenance patientsmight reflect a preference for a different effect,rather than an inadequate methadone dose. Itmay be the case that non-prescribed drugs areused by some to enhance the effect of metha-done. For instance, concurrent administration ofdiazepam (valium) and methadone reportedlyinduces an unusual sense of well-being similar toan "opiate high".̂ '"^^ In addition, benzodi-azepines taken in combination with cycUzine(marzine) and alcohol have been reported toreduce the quantity of the opiate reqiiired.''

Our data suggest that methadone is, at best,only a treatment for opiate dependence andshould not be expected to significantly changethe use of other drug groups.

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