Substitution for substance dependence is the medically prescribed replacement of a dependence-producing substance with a less harmful drug with the same or similar mechanism of action. The combination of substitution with medical, psychological, and social work support is called substitution-assisted treatment (SGB). Treatment goals of SGB are to reduce mortality and risk of new infections, improve physical and mental health, social integration, and quality of life. Opioid agonists approved for substitution include methadone, buprenorphine (Subutex®) and, more recently, slow-release morphine (Sevre-long®). Advantages and disadvantages of the individual substances are explained from a clinical perspective.
In Switzerland, the Federal Office of Public Health (FOPH) estimates that 22,000-27,000 people are dependent on opioids. In 2011, approximately 18,000 people were in substitution-assisted treatment with methadone or other opioids [1], and nearly 1400 were receiving heroin-assisted treatment [2].
Due to the high rates of comorbid somatic (HIV, HCV infections) and mental illnesses (such as post-traumatic and affective disorders or disorders from the schizophrenic spectrum), which can contribute to the chronification of substance dependence, it is recommended that patients be offered additional medical, psychological and social work support in addition to substitution as basic treatment.
The combination of these services is called substitution assisted treatment (SGB). It is recommended in various international guidelines (World Health Organization WHO [3], National Institute for Health and Clinical Excellence NICE) for the treatment of opioid dependence due to its well-documented efficacy with respect to the therapeutic goals listed below. The goals of such treatment are to reduce mortality and the risk of new additional infectious diseases, improve physical and mental health, social integration, and quality of life. An SGB is intended to transform an unstable, decompensated dependence into a stable, compensated dependence. This is a cost-effective measure from the point of view of health economics and is one of the benefits provided by mandatory health insurance. Admission to substitution treatment should be low-threshold in order to provide basic care for opioid-dependent people as comprehensively as possible.
Clinically relevant aspects of pharmacotherapy
In 2012, the Swiss Society of Addiction Medicine SSAM, on behalf of the FOPH, published an updated detailed version of the “Medical recommendations for substitution-assisted treatment (SGB) for opioid dependence” [4], completed by an abridged version published by the FOPH [5]. Based on these texts, a brief overview of clinically relevant aspects of pharmacotherapy in substitution treatment will be provided.
The criterion for indication of substitution with opioid agonists is the presence of opioid dependence according to ICD-10 or DSM IV. Adolescent age is not a contraindication. For pregnant opioid addicts, substitution treatment is highly recommended, since in the case of illegal use, the different substance concentrations, toxic admixtures (extender) to the active substance and the often desolate social situation lead to high complication rates for expectant mothers and children.
Before starting substitution treatment, the most detailed possible medical history and somatic and psychological status should be obtained. A urine sample indicates recent use. Blood sampling with determination of hematologic, hepatic, and virologic parameters is also recommended. An ECG is indicated if risk factors are present. If these examinations are not possible immediately, they should be made up during the course. Further investigations (pregnancy test, serologies of sexually transmitted diseases, tuberculosis) should be offered depending on the patient’s history and clinical condition.
Substances available
In Switzerland, methadone, buprenorphine (Subutex®) and the slow-release oral morphine ( [SROM]; Sevre-Long®), which has been approved for substitution treatment since last year, are different substances that presumably do not differ in terms of retention in treatment [6,7], but mainly in terms of their side-effect profile. In addition, there is the option of substitution with diacetylmorphine (Diaphin®), which can be considered after two failed substitution or abstinence-oriented treatments. From a therapeutic point of view, this expanded range of different opioids for substitution in Switzerland provides a good basis for selecting the best possible substance for treatment in each individual case. In the following, the various substances and their application in clinical practice will be discussed:
Methadone: Methadone is a complete opioid agonist, with the desired effect for substitution coming from the levorotatory isomer of the racemate normally used in Switzerland. When taken orally, the peak effect is expected after three to four hours. The plasma half-life is about 25 hours, which is why it can be taken once a day. Methadone accumulates in the body when taken regularly, and steady-state is reached after about a week. This must be taken into account at the beginning of the treatment, since deaths from too high an initial dose can occur, on the one hand, through acute poisoning in the absence of tolerance and, on the other hand, also after several days through cumulative overdose. The risk of intoxication is increased by the simultaneous consumption of sedating substances such as alcohol and benzodiazepines. Because the lethal dose varies from individual to individual and sometimes depends on genetic factors, induction of treatment is at the lowest possible doses that are not lethal even in opioid intolerant patients. In practice, substitution treatments are started with a maximum of 30 mg of methadone even if tolerance is given. If there is no objective or subjective evidence of sedation three to four hours after ingestion, but pronounced withdrawal symptoms still exist, the dose can be increased cautiously. Individual dose determination is based on withdrawal symptoms and existing co-use.
Methadone is mainly broken down in the liver via the cytochrome P450 system and excreted via the kidney and bile. Metabolism is subject to great genetic variability. In patients with a very fast metabolism (“fast metabolizers”), methadone is broken down within a few hours, so that withdrawal symptoms may occur despite relatively high doses. In these cases, it makes sense to spread the intake throughout the day before increasing the methadone dose further. When concomitantly prescribing drugs that affect the cytochrome P450 system (e.g., carbamazepine, rifampicin, efavirenz, etc.), their interaction potential must be taken into account and the methadone dose adjusted as appropriate.
The most important side effects of methadone are respiratory depression, constipation and nausea due to the slowed intestinal transit, excessive sweating (if necessary. treatable by aluminum chloride hexahydrate in solution or biperiden [Akineton®]) as well as the dose-dependent prolongation of the QTc time, which can rarely lead to life-threatening cardiac arrhythmias. Therefore, with high methadone doses, the presence of cardiac risk factors, and the use of other medications that also have the potential to prolong the QTc interval, an ECG should be performed and, if necessary, a switch to SROM should be made.
Buprenorphine (Subutex®): Buprenorphine is a partial opioid agonist/antagonist that has very little effect when taken orally due to the high first-pass effect of the liver and is therefore administered sublingually. Due to its high affinity for the opioid receptor, it displaces recently ingested opioids from receptor binding, so that withdrawal symptoms can be induced. Thanks to the wide therapeutic range of buprenorphine, which has few pronounced side effects and hardly any respiratory depressive effects even at high doses, rapid up-dosing within a few days is possible and clinically useful.
Withdrawal symptoms should be present before taking buprenorphine. After an initial dose of 2 mg, up to 34 mg may be given on the first day of treatment, and the dose on the second day usually does not exceed 16 mg. Because buprenorphine is broken down through various enzymatic systems, its risk of interaction with other drugs is relatively low. However, in combination with sedating substances such as alcohol or benzodiazepines, there is a risk of respiratory depression. Because buprenorphine has little effect on cardiac electrical conduction, it can be used as an alternative to methadone for prolonged QTc time.
Oral sustained-release morphine (SROM): SROM Sevre-Long®, a pain medication that has also been used off-label for substitution in the past when indicated, received approval in Switzerland in 2013 for substitution in opioid dependence. Morphine is a complete opioid agonist. Despite the short plasma half-life of its metabolites, stable plasma levels can be achieved due to the sustained-release formulation, theoretically allowing once-daily dosing. The peak effect is expected after about six hours. As with methadone, the risk of intoxication is increased by concomitant use of sedating substances. Since morphine is broken down by glucoronidation, drug-drug interactions are unlikely to occur. Morphine also has no effect on cardiac electrical conduction, which is why it is preferable to methadone in the high-dose range for QTc time prolongation.
In a recently published study, morphine was shown to be non-inferior to methadone in reducing heroin use [6]. Some patients also reported improvement in depressive and anxiety symptoms and physical well-being with morphine [8]. There also appear to be benefits with morphine substitution in some patients in terms of reduced heroin craving and withdrawal symptoms, reduction in body weight, better social functioning, and improved sleep quality [9]. In addition, there is evidence that in some patients typical methadone side effects such as excessive sweating, constipation, loss of libido, nausea, increased thirst, dry mouth, and headache may be reduced with morphine substitution [10].
The Swiss Drug Compendium recommends that an initial dose of 200 mg be administered to opoid-dependent patients whose tolerance has not been secured as part of a pre-existing substitution treatment. After reaching the maximum concentration, a cautious dose increase may be applied. Maintenance doses are 500-800 mg, with considerable downward and upward variation possible depending on the clinic.
Conversions
In current practice in Switzerland, substitution treatment is rarely started directly with sustained-release morphine; in most cases, a switch from methadone to SROM is made. Regarding the equivalent doses of methadone to SROM, the literature varies from 1:4 [10] to 1:8 [11]. At low doses of methadone, the conversion factor is more likely to be 1:4, whereas at higher doses, the conversion factor is more likely to be 1:6 or 1:8. The adequate dose is determined based on the clinic and in collaboration with the patient. Especially for methadone “fast metabolizers”, the maintenance dose of SROM is usually considerably lower than expected by conversion due to the different degradation pathway.
Conversion from methadone to SROM and vice versa can be made from one day to the next using the conversion factors provided. An alternative is a staged approach in which half the dose is replaced initially and, over the course of a few days, the switch is completed based on clinical impression and patient input.
If, due to clinical circumstances or at the patient’s request, a change in substitution medication from a pure agonist to a partial agonist/antagonist (and vice versa) is indicated, there are several points to consider:
If buprenorphine is substituted, methadone or SROM should not be taken until clear withdrawal symptoms are present.
Switching from methadone or SROM to buprenorphine is more difficult. It is recommended that the dose initially be tapered to 30 mg methadone equivalent or less. After a sufficiently long waiting period of more than 24 hours, buprenorphine can be taken without causing withdrawal symptoms.
After switching from buprenorphine to methadone/SROM (and vice versa), it is important to determine the adequate dosage clinically; it is not possible to specify a conversion factor.
The various pharmacological treatment options presented here in the context of an SGB, which have currently been expanded by the approval of sustained-release morphine preparations, should make it increasingly possible in the future to meet the need for individualized treatment of patients with opioid dependence.
Med. pract. Nicole Deyhle
Literature:
- Federal Office of Public Health: The National Methadone Statistics 2011. www.bag.admin.ch/themen/drogen/00042/00632/06217/index.html?lang=de4.
- Addiction Switzerland: heroin assisted treatment. www.suchtschweiz.ch/infos-und-fakten/heroin/behandlung/heroingestuetzte-behandlung.
- WHO: Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. www.who.int/substance_abuse/publications/Opioid_dependence_guidelines.pdf?ua=1.
- SSAM: Medical Recommendations for Substitution-Based Treatment (SGB) for Opioid Dependence 2012.%20SGB_2012_FINAL_05%.
- FOPH: Substitution-Assisted Treatment. www.bag.admin.ch/themen/drogen/00042/00629/00798/index.html?lang=de.
- Beck T, et al: Maintenance treatment for opioid dependence with slow release oral morphine: a randomized cross over, non-inferiority study versus methadone. Addiction 2014; 109: 617-626.
- Ferri M, et al: Slow-release oral morphine as maintenance therapy for opioid dependence. Cochrane Database Syst Rev 2013.
- Eder H, et al: Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction 2005; 100: 1101-1109.
- Mitchell TB, et al: Slow-release oral morphine versus methadone: a crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Addiction 2004; 99: 940-945.
- Sherman JP: Managing heroin addiction with a long acting morphine product (Kapanol). The Medical Journal of Australia 1996 Aug 19; 165(4): 239.
- Kastelic A, Dubajic G, Strbad E: Slow-release oral morphine for maintenance treatment of opioid addicts intolerant to methadone or with inadequate withdrawal suppression. Addiction 2008; 103: 1837-1846.
InFo NEUROLOGY & PSYCHIATRY 2014; 12(4): 18-20.
