Chapter 3

DETERMINATION AND PHARMACOKINETICS OF DEXTROMORAMIDE IN METHADONE MAINTENANCE TREATMENT

Jan G.R. Ufkes¹, Jan W. de Vos¹, Giel H.A. van Brussel²

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

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

Submitted to:

?

Since the introduction of the methadone maintenance treatment (MMT) in the late sixties, many studies have been conducted to establish the relation between the pharmacokinetics of methadone and its clinical effect, i.e. reduction of craving, reduction of additional use of other drugs or reduction of HIV infections. Unfortunately those studies have not led to a general consensus with regard to well-defined dosage schedules related to clinical and therapeutic efficacy. In a recent study even a significant relationship was found between higher methadone dose and higher craving levels in several subjects on MMT (de Vos et al., 1995; de Vos et al., 1996a; de Vos et al., 1996b). So it has been recognised that not all MMT participants are equally satisfied with methadone as a replacement for or adjuvant to their illicit opiate use. Their displeasure is expressed by continued additional heroin or other drug(s) use, continued requests for higher dosages of methadone and/or low treatment retention rates.

On account of statutory and practical restrictions to use heroin as adjuvant in such MMT participants the Amsterdam Municipal Health Department (GG&GD) decided to use dextromoramide (Palfium®) in their MMT program experimentally. The choice using dextromoramide was also made on current rumours from local drug-scenes regarding the euphoric effect of dextromoramide being similar to that of heroin.

Dextromoramide was introduced in 1956 (Janssen, 1956) as a synthetic opiate related to methadone and dextropropoxyphene. The medical use, mainly as an analgesic during surgery, became rather limited due to its addiction liability (Seymour-Shove and Wilson, 1967). Although known as a short-acting opiate with strong analgesic and lipophilic properties, only few pharmacokinetic studies have been performed on dextromoramide so far. In surgical patients the pharmacokinetics of intravenously injected dextromoramide in a bolus of 80 μg·kg^-1 were studied (Lançon et al., 1989). In five out of nine patients a two-compartment model best fitted the results, whereas a three-compartment model was the best for the other four. The mean elimination half-life was 215 ± 78 min. In another study nine preoperative patients were given a single oral dose of 7.5 mg dextromoramide (Pagani et al., 1989). Peak concentrations occurred between 0.5 and 4.0 h, whereas the elimination half-life values differed from 1.5 - 21.8 h.

As far as we know from literature no pharmacokinetic data were published on dextromoramide as adjuvant in MMT. The aim of this study was to develop an analytical procedure using HPLC to determine dextromoramide and methadone concentrations in plasma simultaneously, which enabled us to supplement incomplete pharmacokinetic data on dextromoramide in MMT. In this study dextromoramide was used exclusively as an adjuvant therapy for subjects with an ongoing opiate addiction history despite multitreatment. The experimental character of the dextromoramide supplementation, performed in a closed metabolic ward under strictly controlled circumstances, restricted this study to a maximum entry of six subjects.

Methods

Subjects

Six long-term opiate addicts, each on MMT for many years, joined our study on a voluntary basis after their written informed consent. The study, performed in a closed metabolic ward (Jellinek Centrum, Amsterdam), which completely excluded illicit methadone or other drug supplementation, involved two days during which the first day was used for administration of dextromoramide and blood sampling. Standardized meals were supplied at fixed times. All participants were male with a mean age of 47 years (range 35-65 year, see Table 1) and were subjected to physical examination.

Table 1 Subject characteristics

sub. no.	sex m/f	age y	weight kg	MMT dose mg·day^-1	other drug use
1	m	40	85	100	heroin
2	m	51	59	70	heroin
3	m	35	65	60	heroin, oxazepam
4	m	65	59	65	cocaine
5	m	55	59	70	heroin, cocaine
6	m	36	94	70	heroin, chlordiazepoxide

Drug administration and blood sampling

The six subjects in the study were prescribed various daily amounts of d,l-methadone HCl (Brocades, Leiderdorp, The Netherlands), prepared as a methadone linctus of 5 mg·ml^-1, depending on the previous amount of opiate use. The daily MMT dose ranged from 60-100 mg methadone, see Table 1. On the day of blood sampling the dose was diminished according to the amount of dextromoramide given. They received the methadone dose (range 30-65 mg methadone HCl, see Table 2) in the morning after a light standardized meal. Dextromoramide (Palfium®, Dagra Pharma, The Netherlands) was administered as a tablet in doses of 5 or 10 mg immediately after the methadone ingestion. Within 6-7 houres 7-8 blood samples (10 ml) were taken by venipuncture into heparinized tubes. The blood samples were immediately centrifuged during 10 min at 1500 g. The supernatant plasma was stored frozen at -25°C until required for analysis.

Extraction procedure and sample preparation

Subject plasma (0.5 ml) was added with 100 μl methanol, 50 μl trihexyphenidyl HCl (2 μg·ml^-1) as internal standard (IS) to a stoppered glass tube and alkalized with 0.5 ml 2M K₂CO₃. This mixture was extracted into 3.5 ml of n-hexane by gently agitating for at least 120 min at room temperature. After centrifugation (1500 g for 5 min) the content of the tube was chilled to -25°C, which enabled us to separate the unfrozen upper layer (n-hexane layer) from the frozen lower layer. The n-hexane layer was evaporated to dryness under a gentle stream of dry nitrogen. The dry residue was redissolved in 100 μl KH₂phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v). In order to prepare calibration curves the same procedure was performed using plasma from healthy, no drugs using volunteers which was spiked with methadone HCl and dextromoramide tartrate (Janssen-Cilag, Tilburg, The Netherlands) in a concentration range corresponding with 8-400 ng·ml^-1.

Table 2 Analytical data sets for the 6 subjects

sub. no.	dextromoramide				methadone
	dose mg	Cmax ng·ml^-1	tmax h:min	AUC(o-6h) μg·h·l^-1	dose mg	Css ng·ml^-1	Cmax ng·ml^-1	tmax h:min	AUC(0-6h) μg·h·l^-1
1	5	131	1:46	378	60	99	263	3:57	1012
2	5	52	0:50	160	50	181	269	2:31	1334
3	5	171	1:26	338	40	490	673	1:26	2898
4	5	126	1:42	599	65	435	1021	3:39	4417
5	10	194	1:00	489	30	178	184	0:25	527
6	10	135	0:56	238	65	269	570	1:52	2604

Analytical equipment

The HPLC system consisted of a HP 1050 Series Quarternary Pump and Variable Wavelength Detector (Hewlett Packard, USA), a Model 7125 Sample Injector (Rheodyne, USA) fitted with a 50 μl loop and a HP 3395 Integrator (Hewlett Packard, USA) in combination with a BD41 Kipp Recorder (Kipp & Zonen, Delft, The Netherlands). Separation was performed on a Supelcosil LC-ABZ column (50x4.6 mm ID) packed with 5-μm-diameter particles and protected by a 20-mm Supelguard column (Supelco, USA). The mobile phase consisted of KH₂phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v). The flow rate was set at 1.5 ml·min^-1, with UV detection at 206 nm. The analytical procedure was performed in an air-conditioned room at about 20°C.

Calibration and calculations

Solutions of dextromoramide tartrate and methadone HCl in KH₂phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v), were injected into the HPLC apparatus in order to assess detector linearity in a concentration range corresponding with 2-500 ng·ml^-1. Peak height was plotted against the amount of compound injected.

The dextromoramide and methadone levels in the plasma of our subjects were calculated by comparing the UV absorption values (peak heights) of the extracted subject samples with those of the extracted spiked plasma samples (calibration curves) using the internal standard method (Lindsay, 1992).

Recovery values were calculated by comparing the UV absorption values of the extracted spiked plasma samples with those of the unextracted standard solutions of methadone HCl and dextromoramide tartrate in KH₂phosphate buffer (25 mM, pH 2.5) mixed with acetonitrile (80:20, v/v) in the concentration range corresponding with 8-400 ng·ml^-1.

The area under the plasma concentration-time curve during the dosing interval (AUC_(0-6h)), for each subject was calculated by the trapezoid rule (Gibaldi and Perrier, 1982).

Time to peak concentration (t_max) of dextromoramide and methadone for each subject was the period (h:min) between the administration at time 0 and the peak concentration (C_max) detected of dextromoramide and methadone, respectively.

The steady-state concentration (C_ss) of methadone was considered as the plasma concentration just before the methadone administration.

By means of the method of residuals (Gibaldi and Perrier, 1982), values of absorption rate constant (k_a), elimination rate constant (k_el) and distribution volume (V) were estimated. Using these values in Scientist® (version 2.0), an integrated computerprogram with a nonlinear curve-fitting module for the assessment of pharmacokinetic parameters, the data from plasma concentration measurements were fitted according to a two-exponential (one-compartment model) or three-exponential equation (two-compartment model). To select the most appropriate model Scientist® uses a criterion based on the 'Akaike Information Criterion' (Akaike, 1976). Additionally, the area under the plasma concentration-time curve (AUC_0-¥), absorption rate constant (k_a), absorption half-life (t_½a), elimination rate constant (k_el), elimination half-life (t_½el), distribution volume (V) and body clearance (Cl) were calculated by the computer using the appropriate formula (Gibaldi and Perrier, 1982).

Statistics

Data were expressed as the mean (SD) or the 95% confidence interval as appropriate. The paired t-test was used to compare t_max values for methadone with those for dextromoramide. Linear regression analysis was performed to test linearity of the calibration curves.

Results and discussion

Extraction procedure and HPLC-assay validation

The analytical method described above to determine dextromoramide and methadone in plasma simultaneously, meets the criteria for use in clinical pharmacological studies. The method was based on a previously developed reverse-phase HPLC technique to monitor methadone and its primary metabolite in plasma simultaneously (de Vos et al., 1995).

The extent of recovery after extraction appeared to be highly dependent of (in order of importance): (1) the polarity of the organic solvent used in the extraction procedure: n-hexane was the best solvent by far; (2) time of agitation of the extraction mixture: at least 120 min of agitation was necessary for reasonable recoveries ; (3) the amount of methanol (100 μl) added to the plasma sample; 50 μl or less caused lower recovery values. Variation of the pH (>10.0 up to 12) at which the extraction was performed or silanization of the glass tubes were of minor importance. After optimization the calculated recovery values were 79.7 % (7.2), n=20 for dextromoramide, 78.0 % (7.9), n=17 for methadone and 81.3 % (5.2), n=69 for IS. It can be concluded that the extraction procedure is simple and economical and indicates good reproducibility.

Fig. 1 Chromatograms of (a) standard solution of dextromoramide tartrate, methadone HCl and trihexyphenidyl HCl in a buffer-acetonitrile mixture (80:20, v/v), (b) extracted plasma spiked with dextromoramide tartrate, methadone HCl and trihexyphenidyl HCl and (c) extracted plasma from one of the subjects spiked with trihexyphenydyl HCl. Peaks: 1 = trihexyphenidyl (IS), 2 = dextromoramide, 3 = methadone.

The HPLC-assay was found to be both sensitive and specific for both methadone and dextromoramide. Figure 1 illustrates the chromatograms obtained from unextracted standard solution (a), extracted plasma spiked with dextromoramide tartrate, methadone HCl and IS (b) and extracted plasma from one of our subjects (c). Retention times for IS, dextromoramide and methadone were between 5.5 and 9 min. Detection limits in plasma (signal to noise ratio at least 3) appeared to be about 6 ng·ml^-1 for dextromoramide or methadone. The calibration curves for both dextromoramide and methadone in plasma showed linearity (r³0.994) in the concentration range corresponding with 8-400 ng.ml^-1.

Pharmacokinetics

Figure 2 shows a representative plasma concentration-time curve for dextromoramide and methadone (subject 6) after the oral ingestion of 10 mg dextromoramide 9 (as tartrate) and 65 mg methadone HCl at time 0 (9:00 a.m.). As can be seen the time to peak concentration of dextromoramide is considerably shorter than the one of the methadone curve.

Fig. 2 Observed plasma concentrations of dextromoramide (•) and methadone (m) in subject 6 after the oral ingestion of 10 mg dextromoramide (as tartrate) and 65 mg methadone HCl. The solid line represents the best fitted curve calculated by Scientist® according to an one-compartment model.

The six data sets, including steady-state concentration (C_ss) for methadone, peak concentration (C_max), time to peak concentration (t_max) and AUC_(0-6h) for dextromoramide and methadone, are shown in Table 2. In 5 out of the 6 subjects dextromoramide showed a considerable faster gastro-intestinal absorption than methadone; the mean values of t_max for methadone differed significantly (p = 0.027, paired t-test) from those of dextromoramide.

The pharmacokinetic parameters for dextromoramide calculated by the computer program are shown in Table 3. In our calculations we assumed a bioavailibility of 1.0; however, this is highly questionable, because the bioavailibility of orally administered dextromoramide has not been assessed in studies before. After curve-fitting the model selection criterion computed by Scientist® preferred clearly a two-exponential equation (one-compartment model) to a three-exponential equation (two-compartment model) in all subjects.

The mean elimination half-life of dextromoramide appeared to be 1:11 h:min (71 min). This value is considerably shorter as compared to elimination half-life values established in other studies (Lançon et al., 1989; Pagani et al., 1989). However, these studies were not performed under circumstances which were comparable with our study. Using surgical patients who were not addicted to opiates or any other drug in stead of polydrug-users for many years on MMT, may explain this difference. It is well-known that intensive use of drugs from various pharmacological origin for years can be an important factor for hepatic enzyme-induction resulting in shorter elimination half-life values of agents which are metabolized in the liver such as dextromoramide. Similar differences in subject population may also explain the different disposition of dextromoramide as compared to that found in other studies. The pharmacokinetics of dextromoramide in our 6 subjects are best described using an one-compartment model, whereas in many surgical patients a two- or even a three-compartment model best fitted the results (Lançon et al., 1989; Pagani et al., 1989).

Table 3 Pharmacokinetics of dextromoramide including the computer calculated parameters with an assumed bioavailibility of 1.0; after curve-fitting a two-exponential equation (one-compartment model) best describes the analytical data set in all subjects

sub. no.	AUC(o-¥) μg·h·l^-1	ka h^‑1	t½a h:min	kel h^-1	t½el h:min	V l·kg^‑1	Cl ml·min^-1·kg^‑1
1	423	0.75	0:55	0.75	0:55	0.18	2.31
2	177	1.49	0:28	0.45	1:32	1.06	7.94
3	353	1.13	0:37	1.13	0:37	0.19	3.65
4	922	0.62	1:07	0.27	2:32	0.34	1.52
5	502	1.27	0:33	0.75	0:55	0.45	5.59
6	238	1.36	0:31	1.36	0:31	0.33	7.45
Mean		1.10	0:42	0.78	1:11	0.42	4.74
95% confidence intervals		0.74-1.46	0:25-0:59	0.34-1.22	0:23-1:59	0.09-0.75	1.94-7.54

Chapter 8

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 (r_s) 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, r_s = .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, r_s = -.89; p = .02 and r_s = -.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.