Chapter        6

 

THE USE OF DEXTROMORAMIDE AS ADJUVANT IN METHADONE MAINTENANCE TREATMENT TREATMENT

 

Jan W. de Vos1, Jan G.R. Ufkes1, Wim van den Brink2, Freek A. de Wolff3, Giel H.A. van Brussel4

 

1 Department of Pharmacology, University of Amsterdam, Meibergdreef 15, 1105 AZ  Amsterdam, The Netherlands.

2 The Amsterdam Institute for Addiction Research, Jacob Obrechtstraat 92, 1017 KR  Amsterdam, The Netherlands.

 

 

4 GG&GD Amsterdam Section GGZ, Drugdepartment, Valckenierstraat 2, 1018 XG  Amsterdam, The Netherlands.

 

 

Submitted to:

 

Addiction Research

 


In the treatment of opiate addiction methadone has an important role. Besides the prevention of opiate abstinence symptoms, methadone alleviates opiate craving and blocks heroin induced euphoria (Dole and Nyswander, 1965). However, additional drug use among methadone maintenance treatment (MMT) patients in Amsterdam is still very common (Hartgers et al., 1992). Continued opiate craving among long-term MMT patients, who are adequately dosed with methadone, has been reported (Loimer and Schmid, 1992; de Vos et al., 1996). Although reports have been presented indicating the necessity for further scientific research towards (experimentally) using heroin in the MMT programs in the Netherlands, prescription of heroin is still prohibited (Gezondheidsraad, 1995).

In the search for alternatives for heroin as a maintenance drug for illegal heroin, both injectable morphine and injectable methadone have been used. Both have the disadvantage that they are only suited for intravenous drug users and do not seem to resemble the effect that heroin produces in heroin addicts (Derks, 1990; Jongerius et al., 1994).

In 1995 the Amsterdam municipal health department has started using dextromoramide in their MMT program. The analgetic and lipophilic properties of dextromoramide and its strong resemblance with heroin made it a potential alternative for heroin as a substitution for methadone. The short half-life of dextromoramide requires the continuation of methadone administration to avoid occurrence of opiate abstinence symptoms. Dextromoramide, a synthetic opiate, was developed by Janssen in 1956 (Janssen, 1956). The analgesic potency of dextromoramide has been determined between 2 (Pagani et al., 1989) and 5 (Kintz et al., 1989; Lançon et al., 1989) times that of morphine.

Hypothetically, the administration of dextromoramide besides the methadone maintenance dose, should be able to eliminate the occurrence and persistance of opiate craving among addicts who persist in using additional heroin besides their MMT dose. A study was conducted to establish both the pharmacokinetics of dextromoramide and the effects of dextromoramide addition besides MMT on the level and patterns of subjectively experienced opiate craving. The results of the pharmacokinetic part of the study have been published elsewhere (Ufkes et al., submitted). In the present study the effects of dextromoramide addition besides MMT on the level and patterns of craving are described.

 

 

Methods

 

Subjects

 


The study includes 6 subjects, who were randomly drafted from a selected group of 26 MMT clients who indicated their wish to receive dextromoramide. All subjects in the selected group received methadone besides the dextromoramide. The selection criteria for dextromoramide suppletion was based on: voluntary application, a history of irreversible heroin use besides MMT and uncontrollable drug related harm. The randomly selected study subjects (n = 6) were admitted to a closed metabolic ward of the Jellinek clinic. All were male with a mean age of 47 years (range 35 - 65). They entered this study with written informed consent. Subjects entered the clinic for a minimum period of two days. On the first day dextromoramide was administrated and blood samples were taken. The first and the second day were used to sample craving data.

 

Craving

 

The individual level of opiate craving was assessed subjectively using the Experience Sampling Method (Csikszentmihaly and Larson, 1987; de Vries, 1987). This method has been used previously in both ambulatory and clinical addiction research (Kaplan, 1992; de Vos et al., 1996). The subjects received the ESM questionnaire during their visit to the drug dispensary. The questionnaire contains six seven-point Likert scale questions to assess craving; (1) "Did you think about using?", (2) "Did you feel stoned?", (3) "Were you in control of yourself?", (4) "Did you feel restless?", (5) "Did you need dope quickly?", and (6) "Did you feel the need to use dope?". The second and third questions were conceived as 'negative' indicators. The first, fourth, fifth and sixth questions are positive indicators. At random moments (n = 8) during the first day (from 9 am to 10 pm) and on the second day (n = 6, from 9 am to 5 pm) a signal from a remote controlled 'buzzer' prompted a self-report. Around the period of dextromoramide administration until the expected decay of the dextromoramide plasma concentration (on day 1), approximately 6 self-reports were prompted. The two raw item scores for the negative items were subtracted from the total raw item score of the three positive items. The theoretical craving score ranges from -10 (absence of craving) to 26 (extreme craving). The craving data were plotted in time together with the dextromoramide and methadone plasma concentrations. Craving patterns and their association with drug administration time and methadone plasma concentrations were observed. Minimum, maximum and mean values of craving during the dextromoramide plasma sampling period were separately assessed.

 

Methadone and dextromoramide dosing

 

The daily doses of methadone-HCl (Symoron®, Brocades, The Netherlands) were prepared as a methadone linctus 5 mg·ml-1. The study subjects received the daily oral methadone dose at about 09:00 am. During the study period the usual methadone dose was diminished based on the addicts expectancy of the effect of dextromoramide (range: 0 - 40 mg methadone less). Dextromoramide (Palfium®, Dagra Pharma, The Netherlands) doses of 5 mg (n = 4) or 10 mg (n = 2) were administered orally and ingested immediately.

 

Statistics

 

Statistical analysis was performed using SPSS-PC (Norusis, 1988) and Excel for Windows. Spearman rank correlations (rs) were used to describe the relationship between the various pharmacokinetic parameters and craving. Group level associations were assessed using t-tests.

 

 

Results

 

Craving patterns

 


From the maximum of 84 ESM responses, a total number of 75 responses (43 on day 1 and 32 on day 2) were returned and assessed. Missing responses were due to the occurence of other activities of the study subjects simultaneous with an ESM prompt.

Several craving patterns could be distinguished during the observation. Among all six subjects, a general decrease of the craving level during the rise of plasma methadone and dextromoramide concentration could be seen. Four subjects (Fig. 1, 4, 5, 6) showed a distinct craving trough, simultaneous with the dextromoramide plasma concentration peak. In one subject (Fig. 2) a craving trough is observed between the dextromoramide and the methadone plasma concentration peak. Three subjects (Fig. 2, 4, 5) showed an increase of the level of craving just before the administration of methadone and dextromoramide. No responses of the level of craving before drug administration from the other three subjects were available.  Between 11 am and 1 pm, a craving trough is seen among 5 subjects (Fig. 1, 2, 4, 5, 6), in one case (Fig. 6) not associated with a methadone or dextromoramide plasma concentration peak.

 

Association between craving and pharmacokinetics

 

The mean level of craving in the time period of dextromoramide measurement was -0.2 (SD 1.6, n = 33), ranging from -1.6 to 2.1. The craving variability in this period ranged from 3 to 19 (mean 10.5, SD 6.7)(see also Table 1). A significant correlation was found between the maximum methadone plasma concentration and the minimum craving level, rs = .89; p = .02. A significant negative correlation exists between both the maximum and the steady-state methadone plasma concentration and the variability of the level of craving, rs = -.89; p = .02 and rs = -.83; p = .04 respectively.

 

 

Discussion

 

The mean methadone dose for all subjects (51.7 mg) is comparable with the mean methadone dose used in Amsterdam MMT programs (52,7 mg 1992)(van Brussel and van Lieshout, 1993). The steady-state plasma methadone concentration varied between 99 and 490 ng·ml-1. In previous studies plasma methadone levels between 100 ng·ml-1 (Bell et al., 1988), 200 ng·ml-1 (Holmstrand et al., 1978) up to 400 ng·ml-1 (Loimer and Schmid, 1992) have been indicated as protective against opiate withdrawal symptoms. This implies that the plasma methadone levels of the study subjects  were adequate to prevent opiate withdrawal symptoms.


The increase of the level of craving just before the administration of methadone and dextromoramide, which was seen in the 3 cases with craving measurement data taken just before the drug administration, was seen in our previous study as well (de Vos et al., 1996). The plasma methadone concentration in these 3 cases at the time of methadone administration is 180, 450 and 180 ng·ml-1 respectively. These 24-hour trough concentrations should be able to prevent opiate withdrawal symptoms. This indicates that the ESM craving measurement does not indicate opiate withdrawal symptoms. A clear opposite relationship exists between the rising of the plasma dextromoramide concentration and a decrease of the craving level in all cases. In four cases, a dextromoramide plasma concentration peak is simultaneous with a distinct craving trough. Although this pattern would be expected with methadone as well, this was not seen. Similar observations were done in a previous study were only methadone was administered and craving was measured simultaneously as well (de Vos et al., 1996).

An increase of both the minimum and the maximum plasma methadone concentration is significantly correlated with a decrease of the lowest measured level of craving. Although a greater variability of the individually experienced craving could imply a greater mean level of craving, this was not found. However, a decrease of both the minimum and the maximum plasma concentration of methadone is significantly correlated with an increase of the variability of the level of craving.

Although the studied sample is to small to make conclusions from these data, some interesting patterns were seen. The clear dose-response relationship between the plasma concentrations and the craving, could be due to the dextromoramide addition since this clear relationship was not seen in previous studies using methadone only. More investigations, using dextromoramide only are necessary to discern for both opiates.


Table 1         Craving

 

 

 

subject

 

max craving

 

min craving

 

craving variability

 

mean craving

 

1

 

3

 

‑7

 

10

 

-1.60 (n=5)

 

2

 

13

 

‑5

 

18

 

2.14 (n=7)

 

3

 

0

 

‑3

 

3

 

-1.33 (n=3)

 

4

 

2

 

‑3

 

5

 

-1.50 (n=6)

 

5

 

10

 

‑9

 

19

 

-0.17 (n=6)

 

6

 

6

 

‑2

 

8

 

1.50 (n=6)

 

mean

 

5.67

 

‑4.83

 

10.5

 

-0.16

 

SD

 

5.01

 

2.71

 

6.66

 

1.63

 

 


Table 2         Pharmacokinetics

 

 

 

 

 

methadone

 

dextromoramide

 

subject

 

dose (mg)

 

Css (ng·ml-1)

 

Cmax (ng·ml-1)

 

dose (mg)

 

Cmax (ng·ml-1)

 

1

 

60

 

99

 

263

 

5

 

131

 

2

 

50

 

181

 

269

 

5

 

52

 

3

 

40

 

490

 

673

 

5

 

171

 

4

 

65

 

435

 

1021

 

5

 

126

 

5

 

30

 

178

 

184

 

10

 

194

 

6

 

65

 

269

 

570

 

10

 

135

 

mean

 

51.67

 

275

 

470

 

6.67

 

135

 

SD

 

14.38

 

156

 

321

 

2.58

 

48

 

 


Fig 1  Plasma concentrations and craving of Subject 1

 

Fig 1. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 11:50 60 mg methadone and 5 mg dextromoramide were administered.


Fig 2  Plasma concentrations and craving of Subject 2

 

 

 

 

 

 

Fig 2. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 10:20 50 mg methadone and 5 mg dextromoramide were administered.


Fig 3  Plasma concentrations and craving of Subject 3

 

 

 

 

Fig 3. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 11:25 40 mg methadone and 5 mg dextromoramide were administered.


Fig 4  Plasma concentrations and craving of Subject 4

 

 

 

Fig 4. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 9:55 65 mg methadone and 5 mg dextromoramide were administered.


Fig 5  Plasma concentrations and craving of Subject 5

 

 

 

 

 

Fig 5. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 10:00 30 mg methadone and at 11:40 10 mg dextromoramide were administered.


Fig 6  Plasma concentrations and craving of Subject 6

 

 

 

 

 

 

Fig 6. X-axis indicates the time. The left y-axis indicates the plasma concentrations of methadone and dextromoramide. The right y-axis indicates the craving level. Plasma methadone measurements are indicated with a -n-. Plasma dextromoramide measurements are indicated with -l-. The craving measurements are indicated with - -­- -. At 9:00 65 mg methadone and 10 mg dextromoramide were administered.