Polydrug abuse
This study found widespread polydrug abuse among OMT patients as 65% of the urine samples tested positive for abused drugs via LC-TOFMS analysis (Table
4). Abused substances were found in all six studied groups of drugs, in order of decreasing occurrence: BZD (48%), amphetamines (42%), cannabis (30%), N-PPM (25%), NPS 8%, and opioids (7%). Polydrug abuse, in terms of the number of groups of abused substances, was significantly more common among Group IA patients than among Group A patients. Group IA patients had more positive urine samples for abused drugs (52% vs.13%), more BZD-positive urine samples (40% vs. 8%) and more amphetamine-positive urine samples (35% vs. 7%) than Group A patients. All the NPS-positive samples, containing alpha-PVP, MPA (methiopropamine), and PV8 (alpha-PHPP, alpha-pyrrolidinoheptiophenone), were provided by Group IA patients. Most of the N-PPM-positive urine samples, containing pregabalin, gabapentin, and quetiapine, were from Group IA patients. In addition, Group IA patients experienced more subjective withdrawal symptoms and cravings for illicit opioids as potential indicators for the dose-adequate rating. Neither the doses of the OMT medicines, nor the methadone blood concentrations, were different between the two groups of patients.
The 40% occurrence of BZD-positive urine samples among patients with inadequate doses is almost the same (38%) as in our previous study among a similar group of OMT patients [
26]. At baseline, 42% of Group IA patients of the present study had a sedative-, hypnotic, or anxiolytic related disorder, whereas 90% of the patients in our previous study [
26] had either BZD abuse or dependence at the baseline. These findings do not exclude the possibility that methadone treatment may trigger the onset or worsening of BZD abuse as pointed out by Chen et al. [
10]. Group IA patients also demonstrated significant co-abuse of BZD and amphetamines. Regarding individual BZD drugs, oxazepam (38%), temazepam (35%), and desmethyldiazepam (28%) were those most commonly found. The number of urine samples positive for abused temazepam and oxazepam would have been lower if these compounds had been considered the metabolites of diazepam. Diazepam has a higher abuse liability than oxazepam [
24,
31], and consequently it is possible that many of the oxazepam-and temazepam-positive urine samples of this study reflect the abuse of diazepam.
Amphetamine-positive urine samples were found significantly more often among Group IA patients (35%) than Group A patients (7%). The importance of prescribing appropriate methadone dosages to indirectly reduce cocaine use has been described in the study by Baumeister et al. [
32]. Their consideration is in line with the present study concerning amphetamine. Group IA patients had two methamphetamine-positive urine samples. An earlier Finnish study found 21% methamphetamine-positive urine samples among OMT patients with irregular attendance to a harm reduction unit, but no methamphetamine-positive urine samples among OMT patients with regular attendance to drug treatment at a rehabilitation clinic [
16]. Regular visits to the clinic are inevitably related to more adequate doses of the OMT medicine than irregular visits. Cocaine is seen in the Finnish drug market [
4], and also among OMT patients [
15,
16], infrequently. Those reports are in line with the negative urine samples of this study regarding the cocaine metabolite benzoylecgonine.
Most of the gabapentinoid (gabapentin and pregabalin)-positive urine samples (17%) were found among Group IA patients. Up to 32% pregabalin-positive urine samples have been found among Finnish OMT patients who irregularly attend drug treatment at a harm reduction unit [
16]. Both gabapentin and pregabalin are approved for the management of neuropathic pain [
33] and it is possible that the abuse of those drugs is related at least partly to control opioid withdrawal symptoms such as pain, unrest, and sleeplessness, but also due to the psychotropic effects of the gabapentinoids [
17]. No gabapentinoids prescribed for somatic diseases were found in this study.
Extremely common misuse of quetiapine among clients of a methadone maintenance program has been reported by McLarnon et al. [
34]. All the three quetiapine-positive urine samples of the present study were provided by Group IA patients. Quetiapine has been reported to increase plasma concentrations of (R)-methadone [
35]. No high-methadone blood concentrations were found in the two methadone patients from our study, who abused quetiapine. These patients demonstrated 0.17 mg/L and 0.29 mg/L methadone corresponding to the 80 mg and 74 mg daily doses, respectively.
The present study found five (8%) NPS-positive urine samples which all were given by Group IA patients. The synthetic cathinones PV8 and alpha-PVP, and the thiophene ring-based structural analog of methamphetamine MPA, were found in three, two, and one sample, respectively. PV8 appeared on the illicit drug market in 2013 as a candidate to replace MDPV [
36]. No MDPV was detected in this study, in contrast to our previous studies among OMT patients [
15,
26]. To our knowledge, this study represents the first report on the abuse of PV8 among OMT patients.
Cannabis-positive urine samples (30%) were found both in Group IA (22%) and in Group A (8%). The present study detected only THC-COOH and no synthetic cannabinoids, similar to previous Finnish studies [
15,
16], although the LC-TOFMS method used in those studies is able to detect many synthetic cannabinoids. The absence of synthetic cannabinoids is likely due to the increased incidence of home growing of cannabis in Finland [
4].
Opioids (7%) were the most seldom-found group of abused substances. Only 2% of urine samples were opioid-positive among Group A patients. Similarly, Finnish OMT patients with regular attendance for drug treatment had 7% opioid-positive urine samples in contrast to 21% opioid-positive urine samples if the attendance of the OMT patients was irregular [
16]. Thus, the primary task of OMT, to prevent abuse of opioids, is well realized when the dose of the OMT medicine is adequate and the OMT patients regularly attend their clinic. However, the three buprenorphine positive urine samples from patients in methadone treatment are alarming because of potential severe withdrawal symptoms caused by the interaction of those substances.
Doses of the OMT medicines and polydrug abuse
No differences were observed in the mean daily doses of methadone or buprenorphine/naloxone between Group IA and Group A patients, i.e., 65 mg vs. 64 mg and 16 mg vs. 15 mg, respectively. The 65 mg mean daily dose of methadone in this study is at the recommended level (60 – 100 mg) according to reported fixed high-dose studies [
19‐
21], but the mean 15 mg daily dose of buprenorphine is somewhat lower than the minimum effective mean daily dose of buprenorphine (16 mg) in terms of suppression of abuse of opioids among heroin-dependent patients [
2]. Nonetheless, smaller doses of OMT medicines have also been effective in reducing substance abuse. In a flexible dose study, Soyka et al. [
23] reported that the mean daily doses of 44–50 mg methadone and 9–12 mg of buprenorphine were related to a significant decrease in substance use. Furthermore, concomitant drug use for all illicit substances decreased with either an 8 mg or 10 mg daily dose of buprenorphine after 12 months in a non-interventional study performed under real-life conditions [
12]. The real life conditions of the study by Apelt et al. [
12] were similar to those of the present study, where even 24 mg and 30 mg daily doses of methadone, and 6 mg and 8 mg daily doses of buprenorphine, were adequate and urine samples were negative for abused substances (Table
5).
Methadone blood concentration and polydrug abuse
No difference was evident in mean methadone trough blood-concentration (0.20 mg/L) between Group IA (0.19 mg/L) and Group A (0.24 mg/L) patients. Two Group IA methadone patients receiving 20 mg and 50 mg daily doses had less than 0.10 mg/L methadone blood concentrations (Table
5). Group IA also included two other methadone patients (60 mg and 76 mg daily doses) whose methadone blood-concentrations were less than 0.10 mg/L. We found that a methadone concentration less than 0.10 mg/L is related to polydrug abuse, thus higher methadone blood concentrations are needed. The mean methadone concentration of this study was lower than the 400 ng/mL reported by D’Aunno et al. [
21]. It is possible that somewhat higher methadone blood-concentrations would have been combined with less polydrug abuse. However, the blood concentration of methadone has large interindividual variation for a given dosage due to the interindividual variability of CYP enzymes and interactions between methadone and several medications [
37]. In addition, both cannabis and BZD can affect methadone blood concentrations [
38]. Therefore, it is interesting that there is no evidence of a greater variability in the blood concentrations of methadone among the patients with polydrug abuse and different psychiatric comorbidities (Table
2).
Strengths and limitations
This study carries several limitations. The cross-sectional design limits making causal and temporal conclusions between the dose adequacy and polydrug abuse among OMT patients. In addition, the substance groups per definition in some way may overlap and may share similar features. Furthermore, the number of patients was relatively small, giving rise to possible statistical type I and II errors.
Regarding the OMT medicines, Group IA patients were more often on methadone than Group A patients. The patients were not randomized to methadone and buprenorphine/naloxone medication at the start of the OMT, and it is possible that patients with more severe opioid dependence were started with methadone. In addition, the total number of buprenorphine/naloxone patients was low.
The occurrence of individual abused substances in urine samples cannot be generalized because substance abuse in different countries is highly variable and dependent on both the area, the period of evaluation, and the target population. The LC-TOFMS method was limited by the content of the database used. Although full high-resolution MS data were acquired, the data analysis protocol mined only for the masses included in the database. If any of the patients were using a drug that is not targeted by the method, it is highly likely that a false negative result would have been obtained. The LC-TOFMS database of this study did not include olanzapine and venlafaxine which both possess abuse liability [
39]. However, this study shows that OMT patients abuse a broad range of illicit and licit substances and it is unlikely that this is only a Finnish feature among OMT patients. Concerning the safety of the OMT, it is important to give the OMT patients the correct information regarding the abused substances because the patients are seldom aware of the actual substances they are abusing [
15]. The uncertainty of the patients concerning their abused substances may partly be related to the psychiatric comorbidities and to impaired memory among methadone or buprenorphine patients using BZD [
40]. Alcohol consumption was not controlled in this study. A third of patients receiving OMT have been found to have increased alcohol consumption and alcohol use disorders [
41]. Furthermore, a recent study by Preston et al. [
42] reports that drinking was associated with heroin and cocaine craving and actual use among patients in methadone maintenance treatment. Thus, the lack of data concerning alcohol consumption is a clear limitation of this study.
Group IA patients demonstrated moderately high mean scores for opioid craving (4.7), whereas Group A patients had quite low mean scores for craving (2.1) on the VAS-scale. Craving may have different roles among those using various substances and craving contains both automatic and cognition-controlled processes [
43,
44]. The VAS-scale may have measured global craving for drugs, although the patients in the present study were advised to focus only on craving due to illegal opioids as the patients had much polydrug abuse and many psychiatric comorbidities. Besides the uncertainty of rating for craving focusing on only opioids, the rating of subjective withdrawal symptoms may have been nonspecific to some extent, because BZD abuse may also exacerbate opioid-specific withdrawal symptoms [
45].
This study failed to consider the actual distress/symptoms related to the comorbid psychiatric disorders or the licit psychotropic medicines prescribed by the attending physicians. Although the occurrence of the drug dependences and the comorbid psychiatric disorders at baseline were not different between Group IA and Group A patients, the actual psychiatric syndrome and the licit psychotropic medicines might have been different between the two groups and consequently might have affected polydrug abuse differently. This study cannot exclude the possibility that some of the abused substances were actually targeted to treat some of the drug dependences or psychiatric disorders. The more than 90% occurrence of comorbid psychiatric disorders of this study by itself is similar to the study of Brooner et al. [
46]. Interestingly, Brooner et al. [
46] found that in methadone maintenance treatment, reductions in psychiatric distress of the patients were unrelated to substance use outcomes.
It is possible that there are important additional factors that are related to the dose adequacy rating and can provide more information about polydrug abuse in OMT. The scores of stability of sense of coherence were similar at baseline and after 1 year among patients in methadone maintenance treatment, but were lower among patients who still abused any drugs compared with patients who did not [
47]. Thus, the relationship between dose adequacy rating and the sense of coherence rating would be an interesting topic in future studies on polydrug abuse among OMT patients.