What's a Kai in Meth
Background: Compared to other stimulants, methamphetamine is assessed as particularly critical with regard to acute complications, the long-term neurotoxic potential and the development of dependency. So far there have been no evidence-based recommendations for action either in Germany or internationally.
Method: A systematic research on the therapy of methamphetamine-related disorders was carried out. A multidisciplinary group of experts developed recommendations based on this in a nominal group process.
Results: The evidence base for the treatment of methamphetamine-related disorders is generally weak. The effectiveness of psychotherapeutic methods, for example cognitive behavioral therapy or contingency management, as well as complex, disorder-specific programs has been well documented in the randomized controlled studies available. It is not clear which method is particularly suitable. Those affected with a substance use diagnosis should in principle receive psychotherapy. Both guided and independent structured sports programs can improve addiction-specific endpoints such as comorbid disorders and should therefore be offered. In comparatively weak studies with small case numbers and high drop-out rates, drug interventions showed little to no effects and are therefore recommended with very limited restrictions - primarily tranquilizers for the short-term treatment of agitation, if necessary also atypical antipsychotics. Substitution attempts such as with methylphenidate or dexamphetamine have so far not shown any reliable results. Sertraline should not be used because of significant adverse drug effects.
Conclusion: Because of the weak evidence base and, in some cases, minor effects, many recommendations received a weak recommendation grade. In the acute situation, a symptom-oriented approach is recommended. Psychotherapy and sport should be offered.
Doctors and staff in clinics, practices and addiction support facilities are increasingly confronted with an increased use of methamphetamine (“meth”, “crystal meth”). This is particularly widespread in some regions of Saxony, Thuringia and Bavaria that are close to the Czech border. In addition, methamphetamine also appears to be common in specific scenes, such as MSM (men who have sex with men). The so-called “chemsex”, ie sexual intercourse under the influence of drugs, is related to the particularly risky form of intravenous consumption (1). Compared to other stimulants, methamphetamine is particularly critical with regard to acute complications, long-term neurotoxic potential and the development of addiction. The treatment of methamphetamine-related disorders is a challenge for multidisciplinary addiction support, but also for first aiders and hospital staff. There is a need for support in this regard, especially since guidelines available from Germany and abroad do not specifically refer to the substance methamphetamine and are largely out of date (2).
On the initiative of the Federal Drug Commissioner, financed by the Federal Ministry of Health and commissioned by the German Medical Association, a panel of experts developed this S3 guideline from April 2015 to September 2016 according to the criteria of the Working Group on Scientific Medical Societies (AWMF). Methodological support was provided by the Medical Center for Quality in the Medicine. The 21 experts involved included clinically active doctors from various disciplines, psychotherapists, nurses, social workers and representatives of self-help (eTable 1, eTable 2). Further experts were called in for specific questions.
The S3 guideline was drawn up in accordance with the AWMF regulations (3). A systematic literature search was carried out in June 2015 in the Cochrane Database, Medline, PSYNDEX and PsycINFO. A hand search was also carried out. All studies and systematic reviews of therapeutic interventions in people with methamphetamine-related disorders from 2000 onwards were included (graphic, eTables 3 and 4, eBox). The evidence was graded according to the scheme of the Oxford Center for Evidence-Based Medicine 2011 and systematic reviews were also assessed according to AMSTAR (Assessing the Methodological Quality of Systematic Reviews). A systematic search for guidelines was carried out in April 2015. Identified guidelines were assessed using the German guideline assessment tool (DELBI). An update research was not carried out. The experts did not bring any further studies into the development process.
Recommendations were agreed in three consensus conferences in a nominal group process. A consensus strength of at least 75% was required. A public consultation took place from May to June 2016.
Possible conflicts of interest of all involved were recorded and discussed according to the guidelines of the AWMF (3). Exclusions were considered unnecessary, and abstentions were decided in individual cases.
The methodological approach, the evidence tables, comments from the consultation and the surveys of conflicts of interest are published in the associated guideline report (2).
348 full texts were viewed and 103 studies were included, 58 of them on drug interventions. Despite randomized controlled trials (RCTs), most publications showed considerable limitations, including small case numbers and high drop-out rates. Abstinence was rarely investigated as the primary endpoint, the amount and frequency of consumption, retention rate (continued therapy) or addictive pressure were more common. In summary, there are few and rather weak indications of the effectiveness of drug interventions in acute and post-acute therapy. In psychotherapy studies, the transferability of some Anglo-American concepts such as reward-based contingency management to Germany is questionable, since the patient's acceptance of the material reinforcements used depends on socio-cultural attitudes and socio-economic living conditions.
Nevertheless, 135 recommendations on the topics of diagnostics, awareness and early intervention, acute therapy, post-acute therapy, comorbidity, special groups of people, relapse prevention and harm reduction were approved, more than two thirds of them unanimously. Because of the limited reliability of the evidence and low effects, many recommendations are weak. The experts only make strong recommendations if there is relative certainty regarding the therapeutic effects, relevant ethical considerations or a description of established good clinical practice. Selected recommendations for therapy are presented below. Treatment planning recommendations are given in Table 1.
In the literature search on the emergency treatment of methamphetamine intoxication, no primary studies but an older, consensus-based guideline of moderate methodological quality were found (4). The recommendations are based on this and on clinical experience.
A person intoxicated with methamphetamine should be cared for in an environment that is as quiet as possible, shielding against irritation and with continuous personal support. Since methamphetamine intoxication is often mixed with consumption, the administration of medication should be avoided as far as possible without adequate monitoring options. If there is an urgent need for treatment due to severe agitation, aggressiveness or psychotic symptoms, benzodiazepines should be used as the first choice. If these alone do not provide adequate sedation, an additional antipsychotic can be considered, especially in the case of delusions and hallucinations.
After intoxication, further psychiatric / addiction medical diagnostics and, if necessary, treatment should be recommended. If methamphetamine addiction is found, inpatient qualified withdrawal treatment should be offered for at least 3 weeks.
Qualified withdrawal treatment
Few studies have been identified on the effectiveness of interventions in skilled withdrawal treatment. The recommendations are based primarily on extrapolations from studies on post-acute treatment and expert opinion.
In the case of a methamphetamine-related disorder, psychotherapeutic methods such as psychoeducation and motivational interviewing should be offered as part of in-patient qualified multimodal withdrawal treatment. No reliable study results are available to compare the individual psychotherapeutic methods in the context of acute therapy. Longitudinally, complex, coordinated intervention packages are probably more promising than the sum of individual interventions (5). For this reason, other psychotherapeutic methods such as behavior therapy or contingency management can already be used in qualified withdrawal treatment in the sense of closely interlinking acute and post-acute treatment.
With regard to drug therapy, existing RCTs have very small case numbers and high drop-out rates. Effects were only seen for secondary endpoints such as addictive pressure or retention rate. The experts therefore recommend - and also against the background of the fundamental off-label use - a cautious use of drugs, whereby tranquilizers, drive-enhancing antidepressants or antipsychotics can be considered depending on the target syndrome (symptom-oriented approach, Table 2). Because of the risk of serotonergic syndrome and the frequently described increased rate of side effects, the guideline strongly advises against selective serotonin reuptake inhibitors (SSRIs) even in the case of depressive symptoms. Dexamphetamine (in the case of multiple unsuccessful withdrawal attempts in the previous history, limited in time and only in an inpatient setting) and acetylcysteine (in the case of pronounced craving) are named as "can" recommendations. In two small RCTs, dexamphetamine showed no effect on consumption reduction, but had a more positive effect on secondary endpoints compared to placebo (retention rate: 86.3 ± 52.2 days versus 48.6 ± 45.4 days; p = 0.014). In a placebo comparison, acetylcysteine improved craving significantly in a very small number of patients (4.57 versus 3.2; p < 0,001). hier="" war="" unter="" anderem="" das="" günstige="" nebenwirkungsprofil="" ausschlaggebend="" für="" die=""> 0,001).>
Post acute therapy
According to experts, post-acute forms of intervention should be offered as seamless further treatment after the withdrawal phase in order to keep and stabilize those affected in the addiction support system.
Psychotherapeutic counseling and treatment offers
As part of the research, 26 RCTs on psychotherapeutic procedures were identified that had a reduction in methamphetamine consumption as the primary endpoint. Abstinence-oriented therapy goals were not explicitly pursued in any of the studies, but (temporary) abstinence was only recorded as a secondary endpoint. Whether the interventions are suitable for promoting abstinence cannot therefore be conclusively assessed on the basis of the available data. There has been evidence of positive effects on, for example, the frequency of consumption, the number of negative urine samples or craving.
Efficacy studies on the following intervention methods were determined:
- motivating conversation
- Promotion of motivation
- Contingency management
- cognitive behavioral therapy
- Acceptance and commitment therapy
- Matrix and FAST ("Family Alternative treatment activities, Self-help and Therapeutic community")
- Stepped care approaches (a needs-based, graduated system of intervention offers from low-threshold education to complex and inpatient therapy approaches)
- community-based approaches.
In all interventions, addiction-specific endpoints such as a reduction in methamphetamine consumption improved significantly compared to baseline and the control group. When comparing different methods, there were seldom significant advantages of a specific approach. An RCT with 229 patients compared a psychotherapy procedure and drug withdrawal treatment with sertraline (6). Contingency management, the applied psychotherapy method, is an intervention method of classical behavior therapy, in which the achievement of agreed behavior such as consumption reduction is reinforced by rewards, for example a voucher. Here, the patients treated with sertraline had a significantly lower retention rate and were significantly less likely to attend relapse prevention. Contingency management showed a significantly higher rate of patients with three consecutive weeks of abstinence (sertraline [25.4%] versus sertraline + contingency management [42.6%] versus contingency management [51.9%] versus placebo [41.8%] , p = 0.035). There was no difference in terms of craving, depression and adherence. However, significantly more side effects (nausea, sexual dysfunction, gastrointestinal and anticholinergic adverse drug reactions) were reported with sertraline.
The guideline authors conclude that the psychotherapeutic offers examined are effective. However, based on the study design, it cannot be deduced whether certain approaches are superior. Complex, disorder-specific approaches like Matrix may be particularly effective. In the RCT on the effectiveness of Matrix (7), the therapeutic effect may have been underestimated, since there the “treatment as usual” of the control group was carried out with a higher dose and intensity.
Therefore, every methamphetamine user with or without a diagnosis of dependency should be given a need / motivational psychotherapeutic counseling or therapy offer. According to the stepped care approach, this should range from low-threshold information, psychoeducation and counseling offers to multimodal consumption reduction or weaning therapy programs. Methamphetamine users who meet the diagnostic criteria for a substance-related disorder should be offered and conveyed behavioral therapy or methamphetamine-specific complex programs, depending on their willingness and availability to reduce consumption or weaning.
The search yielded 58 studies on drug interventions, mostly RCTs, of which only a few were of sufficient methodological quality. Many studies were also carried out in combination with cognitive behavioral therapy (8). Acetylcysteine, antidepressants, anti-epileptics, atypical neuroleptics, calcium antagonists, muscle relaxants, opioid antagonists, psychostimulants, varenicline, cholinesterase inhibitors and citicoline were investigated. None of the examined preparations has approval in Germany for the treatment of methamphetamine addiction.
After weighing the study limitations, the observed effects and possible harm, the experts only made a weak, restricted “can” recommendation for the drive-enhancing antidepressants bupropion and imipramine. A post-hoc analysis of a methodologically adequate RCT (n = 151) showed a slight advantage of bupropion compared to placebo for the duration of abstinence in patients who were already moderately consuming (less than 18 days per month) at baseline. Absolute abstinence for ≥ 2 weeks was 20% versus 7%, ≥ 6 weeks 14% versus 4%, 12 weeks 6% versus 1% (p = 0.0176) (9, 10). Although another, smaller RCT (n = 94) could not confirm these results (11), the experts see here at least the possibility of therapy support for people with low to moderate consumption. For 150 mg imipramine daily, a small RCT (n = 32) showed a significantly higher retention rate compared to 10 mg daily (median 33 days versus 10.5 days) (12, 13).
Sertraline should not be used in methamphetamine-related disorders. A methodologically adequate RCT showed no benefit in the placebo comparison and also a significantly poorer retention rate (38% versus 60%, p = 0.036) and a strong tendency towards poorer abstinence results, measured as 3 consecutive weeks without a positive urine test (34.2% versus 46.8%, p = 0.052) (6).
The experts consider substitution attempts with psychostimulants, although they are pharmacologically plausible, to be insufficiently proven, for example retarded D-amphetamine or retarded methylphenidate. The few RCTs showed considerable deficiencies, the effects were inconsistent and mostly related to secondary endpoints. Such treatment attempts should only be carried out in the context of high-quality clinical studies (more in an inpatient setting). In addition, Modafinil should not be used. An RCT (n = 210, high drop-out rate, low compliance) (14) was unable to show any advantages over placebo with a high risk of interactions (increased effectiveness).
A drug combination treatment with flumazenil, gabapentin and hydroxyzine also showed no effectiveness in an RCT (15) with a simultaneous risk of serious side effects such as epileptic seizures. It should therefore not be used.
The experts do not consider the evidence for all other tested substances to be conclusive enough to make recommendations at all. There is an urgent need for research here.
In three methodologically reliable RCTs, sports therapy had a significantly positive effect on methamphetamine abstinence symptoms such as addictive pressure, but also on accompanying symptoms such as anxiety and depression (16–18). Both guided structured sports programs several times a week with different intensities and a sports program controlled by the patients themselves were examined. Therefore, sports therapy should be offered and conveyed in a supportive manner.
Neurofeedback also improved addiction-specific endpoints and quality of life in an RCT compared to pharmacotherapy alone (19). However, since this is a complex process, the experts give a weak “can” recommendation.
There are no studies on the use of ear acupuncture according to the protocol of the National Accupuncture Detoxification Association (NADA) in methamphetamine users, but positive individual case reports exist. Since it is considered to be extremely low-risk, the experts give a weak “can” recommendation despite the lack of evidence.
Comorbid mental disorders are common in methamphetamine-related disorders, although the relationships are complex and by no means unidirectional. Indications of self-medication arise when methamphetamine is used, for example, to relieve symptoms of depressive disorders as well as anxiety or post-traumatic disorders (1). On the other hand, the consumption of metamphetamine itself can cause psychological symptoms and disorders.
In the opinion of experts, methamphetamine-related disorders and comorbid disorders should preferably be treated in an integrated manner or, if this is not possible, appropriately coordinated. Those affected with a comorbid mental disorder should be offered disorder-specific psychotherapy.
In the following, only special features of the therapy of comorbid diseases in the case of an existing methamphetamine-related disorder are addressed, insofar as they can be derived from the existing literature.
Depression and bipolar disorder
The studies available to date have shown no effectiveness of antidepressants in comorbid depression. There are weak indications of efficacy of limited methodological quality for depressive symptoms for the antipsychotic quetiapine, and very weak indications for the dietary supplements citicoline or creatine. They can also be offered as a therapy attempt for depression or bipolar disorder (20–22). In the case of bipolar disorder, there are also weak indications for the use of risperidone; this can also be offered (20). In the case of dietary supplements, in addition to a not very reliable indication of a benefit, the low potential for harm speaks in favor of the recommendation: In a placebo-controlled RCT (n = 60), the depressive symptoms improved according to the Inventory of Depressive Symptomatology-Clinician Rating (IDS-C ) from 38.8 versus 37.8 at baseline to 26.2 versus 33.1 (p = 0.05) at the end of the study (21). Psychoeducation and sports therapy have proven effective and should be offered (17, 23).
In a methodologically good RCT, sports therapy was also able to reduce anxiety symptoms and should therefore be offered (17).
Attention Deficit Hyperactivity Disorder
The general treatment recommendation for attention deficit hyperactivity disorder regarding methylphenidate is not applicable to patients with comorbid methamphetamine-related disorder. In addition to a possible tolerance to methylphenidate due to the similarity of the chemical structure, the therapy harbors a potential for abuse. Therefore, if there is an indication for pharmacotherapy, atomoxetine or antidepressants such as bupropion, venlafaxine or duloxetine should be given primarily.
Based on clinical experience and case reports, the guideline recommends that addiction-related care for at least one year should follow shortly after post-acute treatment. This is ideally tailored to the needs of those affected and can include psychotherapeutic group or individual therapies, sociotherapeutic offers as well as self-help or sports offers.
The guideline recommends abstinence as the primary therapeutic goal. However, many of those affected cannot or do not (yet) want to achieve this goal. Suitable measures to minimize damage should be recommended to you:
- Consumption reduction
- less harmful forms of consumption, especially no intravenous consumption
- Avoiding dangerous interactions such as serotonin syndrome
- regular diet
- Maintaining dental health
- protected sex.
The systematic research on the therapy of methamphetamine-related disorder has identified evidence on many psychotherapeutic, medicinal and other interventions. However, the experts rate most of the available studies as methodologically inadequate, so that they make many recommendations as expert consensus. In spite of fewer studies (26 RCTs), psychotherapy methods are proven to be of better benefit than the drug-based studies (58 RCTs), i.e. in the reduction of consumption: Behavioral therapeutic interventions, contingency management and combination programs have proven to be effective, although some Anglo-American ones are transferable Concepts on Germany is questionable. There is no empirical answer as to whether psychotherapy can improve the goal of achieving abstinence. Despite a higher number of RCTs, few positive effects on the various aspects of methamphetamine-related disorders were found for drug-based procedures. The authors of the guideline see an urgent need for research.
We would like to thank all authors and external experts of the S3 guideline "Methamphetamine-related disorders": Wolf-Dietrich Braunwarth, Michael Christ, Jürgen Dinger, Henrike Dirks, Janina Dyba, Timo Harfst, Heribert Fleischmann, Peter Jeschke, Marco R. Kesting , Antje Kettner, Michael Klein, Benjamin Löhner, Winfried Looser, Sascha Milin, Josef Mischo, Bernd Mühlbauer, Jeanine Paulick, Niklas Rommel, Ingo Schäfer, Norbert Scherbaum, Katharina Schoett, Frank Schulte-Derne, Jan-Peter Siedentopf, Frank Vilsmeier, Norbert Wittmann, Anne Krampe-Scheidler.
Conflict of interest
Prof. Gouzouli-Mayfrank has received fees for book projects related to the subject of the present work from the publishers Springer, Kohlhammer, Steinkopff and Thieme.
The other authors declare that they have no conflict of interest.
Taken: March 14, 2017, revised version accepted: April 7, 2017
Address for the authors
Prof. Dr. med. Euphrosyne Gouzoulis-Mayfrank
Medical Center for Quality in Medicine (ÄZQ)
Strasse des 17. Juni 106-108
Gouzoulis-Mayfrank E, Härtel-Petri R, Hamdorf W, Havemann-Reinecke U,
Mühlig S, Wodarz N: Clinical practice guideline: Methamphetamine-related disorders.
Dtsch Arztebl Int 2017; 114: 455-61. DOI: 10.3238 / arztebl.2017.0455
The German version of this article is available online:
www.aerzteblatt.de/17m0455 or via QR code
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