Buprenorphin als Antidepressivum

Vorwort
WIRKEN OPIOIDE ANTIPSYCHOTISCH UND BUPRENORPHIN ANTIDEPRESSIV?
Introduction
Abbildung
Methods
Results
Discussion
References

Von Essex Pharma GmbH

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Artikel aus Pub Med.

Weiteres aus Pub Med.
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Lieber Leserinnen und Leser.
Immer wieder erreicht uns Nachricht von depressiven Menschen mit der Frage: eignet Buprenorphin sich als Mittel gegen Depressionen?
Hier seien einige Arbeiten angeführt, zum Teil aus Pub Med, die diese Frage beantworten. Bei Pub. Med. handelt es sich um die Amerikanische öffentliche Bibliothek für Medizin, eine Bibliothek mit weltweit genutzter Datenbank. Aufgrund dieser Arbeiten ist Buprenorphin/Subutex/Temgesic, als Mittel gegen Depressionen verschreibungsfähig. Damit kann ein Patient seinen Arzt auffordern, Buprenorphin/Subutex/Temgesic, zur Behandlung von Depressionen zu verschreiben.

Eine weitere Arbeit von H. M. Emrich, P. Vogt und A. Herz vom Max-Planck Institute für Psychiatrie, zeigt die eindeutig antidepressive Wirkung des Buprenorphins auf. Diese Arbeit, die u.a. im Handbuch für experimentielle Pharmakologie erschienen ist, wird auffallend von der Deutschen Psychiatrie ignoriert. Diese Missachtung ist pragmatisch/politischer Natur. Die heilsamen Aspekte von Opioiden öffentlich anzuerkennen, gilt auch heute noch als gesellschaftlicher und beruflicher Selbstmord...-

INTRACEREBRAL
Die Morphinistenseite

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Buprenorphin bei Depressionen
ebenso wirksam wie trizyklische
Antidepressiva!

Der Wirkstoff Buprenorphin (Handelsname Subutex®) wird
aufgrund seines hohen Sicherheitsprofils als Alternative zu
Methadon bei der Substitutionstherapie opioidabhängiger
Patienten zunehmend angewandt. In Frankreich werden
aktuell über 72 000 Patienten mit Subutex® behandelt, demgegenüber
stehen ca. 6500 Patienten unter Methadonsubstitution.
In Deutschland, wo die Zulassung im Januar 2000
erfolgte, profitierten bereits über 3000 Patienten von der
Substitution mit Subutex®. Neben seinen Vorzügen in der
Substitutionstherapie mit hohem Sicherheitsprofil, vergleichsweise
niedrigem Abhängigkeits- und Nebenwirkungspotential,
sowie variablen Vergabemöglichkeiten (1x täglich,
3 x wöchentlich, "Take-home"), wird der Wirkstoff
Buprenorphin seit Jahren auch auf seine antidepressiven
Eigenschaften hin untersucht.
Bereits 1982 berichteten Emrich et al. von den potenten
antidepressiven Effekten von Buprenorphin. Bodkin et al.
(1995) bestätigten diese Ergebnisse durch ihre eigene Studie
an Patienten mit therapierefraktären, schweren Depressionen.
Auch Schmauss et al. (1987) beschrieben in ihrer
klinischen Untersuchung potente antipsychotische Effekte
von Buprenorphin. Zuletzt berichteten Paetzold et al. (2000),
dass die Detoxifikation mit Buprenorphin und Carbamazepin
gegenüber dem Behandlungsschema Oxazepam/Carbamazepin
eine signifikant bessere Wirkung auf Angst, Depressivität
und Entzugssymptomatik aufwies.
Einer bis dato relativ unbeachteten Publikation von Kosten
et al. (1990) zufolge war die Responsrate depressiver buprenorphinsubstituierter
Patienten mit der depressiver Methadonsubstituierter,
die zusätzlich trizyklische Antidepressiva
verabreicht bekamen, vergleichbar: Kosten et al. untersuchten
40 opioidabhängige Patienten mit Hilfe der validierten
Depressionsfragebögen BDI (Beck Depression Inventory)
und SDS (Short Depression Scale). Die Erhebung wurde vor
Einstellung und 7, 14, 21 und 25 Tage nach Einstellung auf
Buprenorphin durchgeführt. 19 Patienten hatten einen BDIScore
über 10 (Median: 17,1) und einen SDS-Score von 9,6,
die restlichen 21 Patienten einen BDI-Score unter 10. Sowohl
während der ersten Woche als auch im Verlauf der
zweiten Woche konnte ein signifikanter Rückgang depressiver
Symptome bei den buprenorphinsubstituierten Patienten
beobachtet werden (p < 0,05 und p < 0,03). Der SDSScore
reduzierte sich im Mittel um 3,5 Punkte.
Die globale Responsrate von 63% bei alleiniger Gabe von
Buprenorphin war mit der Responsrate von depressiven PaPatienten
vergleichbar, die kombiniert Methadon und trizyklische
Antidepressiva erhielten. Darüber hinaus entwickelte während
der Untersuchung keiner der nichtdepressiven buprenorphinsubstituierten
Patienten eine Depression. Bei methadonsubstituierten
Patienten hingegen sind neu auftretende Depressionen
bei mehr als 20% zu erwarten.
Aufgrund dieser Ergebnisse können folgende Schlussfolgerungen
gezogen werden:
1. Neben seiner Eigenschaft als wirksames Substitutionsmittel
mit hohem Sicherheitsprofil scheint es sich bei Buprenorphin
um ein effektives, schnellwirkendes Antidepressivum
zu handeln. Daher kann es ebenfalls bei
depressiven Opioidabhängigen als Alternative zu Methadon
angesehen werden.
2. Es liegt nahe, dass die Verbesserung der depressiven
Symptomatik bei der Hochrisikopopulation intravenöser
Drogenmissbraucher einen direkten positiven Einfluss
auf die psychosoziale Einstellung des Patienten, das Suizid-
Risiko, den Kokain-Abusus, den Beigebrauch anxiolytischer
Medikamente (z.B. Benzodiazepine) und die
Verbreitung von AIDS hat, insbesondere da Depressionen
den Kurz- als auch Langzeiterfolg einer Substitutionsbehandlung
beeinträchtigen.
Literatur
Bodkin JA, Zornberg GL, Lukas SE, Cole JO (1994): Buprenorphine
treatment of refractory depression. Journal of Clinical Psychopharmacology
15, 49-57
Emrich HM, Vogt P, Herz A (1992): Possible antidepressive effects
of opioids: action of Buprenorphine. Annals New York Academy
of Sciences 398, 108-112
Kosten TR, Morgan C, Kosten TA (1990): Depressive Symptoms
During Buprenorphine Treatment of Opioid Abusers. Journal of
Substance Abuse Treatment 7:51-54
Paetzold W, Eronat V, Seifert J, Emrich HM, Schneider U (2000):
Detoxifikation polytoxikomaner Patienten mit Buprenorphin. Nervenarzt
71, 722-729
Schmauss C, Yassouridis A, Emrich HM (1987): Antipsychotic effect
of buprenorphine in schizophrenia. American Journal of Psychiatry
144 (10), 1340-1342
Dr. med. Peter Förtig
Medical Manager
ESSEX Pharma GmbH

1: Addict Biol. 2005 Jun;10(2):157-64.

Mood and affect during detoxification of opiate addicts: a comparison of
buprenorphine versus methadone.

Seifert J, Metzner C, Paetzold W, Borsutzky M, Ohlmeier M, Passie T, Hauser U,
Becker H, Wiese B, Emrich H, Schneider U.

Department of Clinical Psychiatry and Psychotherapy, Hannover Medical School,
Germany. Seifert.Juergen@mh-hannover.de

Twenty-six in-patients with Diagnostic and Statistical Manual version IV
(DSM-IV) criteria for opioid dependence were selected at random to receive
either a combination of an 11-day low-dose buprenorphine and a 14-day
carbamazepine regimen (n = 14) or a combination of an 11-day methadone and a
14-day carbamazepine regimen (n = 12) in a double-blind, randomized 14-day
in-patient detoxification treatment. Patients with buprenorphine and
carbamazepine showed a significantly better psychological state after the first
and second weeks of treatment. Above all, the buprenorphine-treated patients
demonstrated a less marked tiredness, sensitiveness and depressive state as well
as a more prominent elevated mood during the detoxification process. Seven
non-completers (after 7 days: four of 12 = 33.3%; after 14 days: seven of 12 =
58.3%) were treated with methadone and carbamazepine and five non-completers
(after 7 days: two of 14 = 14.3%; after 14 days: five of 14 = 35.7%) received
buprenorphine and carbamazepine. The difference in the overall dropout rate
after day 14 was not significant. The present study supports the hypothesis that
the combination of buprenorphine and carbamazepine leads to a better clinical
outcome than does a combination of methadone and carbamazepine in the
detoxification of opioid addicts with additional multiple drug abuse. The
buprenorphine and carbamazepine-regimen provides a more effective short-term
relief of affective disturbances than does methadone and carbamazepine. No
severe side effects occurred during the treatment period in both groups.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 16191668 [PubMed - indexed for MEDLINE]

2: Pharmacopsychiatry. 2002 Sep;35(5):159-64.

Detoxification of opiate addicts with multiple drug abuse: a comparison of
buprenorphine vs. methadone.

Seifert J, Metzner C, Paetzold W, Borsutzky M, Passie T, Rollnik J, Wiese B,
Emrich HM, Schneider U.

Department of Clinical Psychiatry and Psychotherapy, Medical School, Hannover,
Germany. Seifert.Juergen@mh-hannover.de

Over the last few years, there has been a growing tendency for opioid addicts to
abuse multiple drugs, although many patients are in substitution therapy with
methadone. Abuse of multiple drugs leads to a more complicated withdrawal
syndrome; it is therefore necessary to investigate new drug strategies as a
treatment for detoxification. Buprenorphine appears to be an effective and safe
drug in opioid-addicted patient detoxification. In this study, we have compared
the short-term efficacy of an 11-day low-dose buprenorphine/14-day carbamazepine
regime [BPN/CBZ] (n = 14) to an 11-day methadone/14-day carbamazepine regime
[MET/CBZ] (n = 12) in a double-dummy, randomized 14-day inpatient detoxification
treatment study. Twenty-six inpatients met the DSM-IV criteria for opioid
dependence and were included in this study. All patients abused various
additional drugs. Fourteen of 26 patients (53.8 %) completed the study. Seven
non-completers (seven of 12 = 58.3 %) were treated with methadone/carbamazepine
and five non-completers (five of 14 = 35.7 %) received
buprenorphine/carbamazepine, but the difference in the dropout rate was not
significant. However, patients with buprenorphine/carbamazepine showed
significantly fewer withdrawal symptoms after the first two weeks of treatment.
The present study supports the hypothesis that buprenorphine/carbamazepine is
more effective than methadone/carbamazepine in detoxification strategies for
opioid addict with additional multiple drug abuse. No severe side effects
occurred during treatment in either group.

Publication Types:
Clinical Trial
Randomized Controlled Trial

PMID: 12237786 [PubMed - indexed for MEDLINE]

3: Nervenarzt. 2000 Sep;71(9):722-9.

[Detoxification of poly-substance abusers with buprenorphine. Effects on affect,
anxiety, and withdrawal symptoms]

[Article in German]

Paetzold W, Eronat V, Seifert J, Holze I, Emrich HM, Schneider U.

Abteilung Klinische Psychiatrie und Psychotherapie, Medizinische Hochschule
Hannover.

We used an open-labeled, 21-day inpatient detoxification treatment to compare
the short-term effects of a 10-day buprenorphine plus 19-day carbamazepine
regimen (n = 15) to a 14-day oxazepam plus 19-day carbamazepine regimen (n = 12)
during rapid detoxification from opioids and other abused drugs. Somatic and
psychopathological changes were assessed using the following rating scales: ASI,
HAMD, SCL-90-R, and SOWS. Eighteen of 27 patients (67%) completed the study.
Four dropouts (27%) were treated with buprenorphine/carbamazepine (BPN/CBZ) and
the other five dropouts (42%) were treated with oxazepam/carbamazepine
(OXA/CBZ). Repeated measures analysis of variance showed that SOWS scores were
significantly less pronounced with BPN-CBZ than with OXA/CBZ. On the first day
of admission, no significant difference in HAMD scores was detected (BPN/CBZ
11.6, BPN/CBZ 1.0). On day 14, HAMD was significantly less pronounced in BPN/CBZ
(3.0) than in OXA/CBZ (6.1). BPN/CBZ showed a significant improvement in the ASI
score on days 7 and 14 compared with OXA/CBZ. Three of nine items of the
SCL-90-R showed a trend toward less pronounced outcome in BPN-CBZ. No severe
side effects occurred during treatment in either group. The
buprenorphine/carbamazepine regimen provided significantly more effective relief
from affect disturbances and withdrawal syndromes than the
oxazepam/carbamazepine regimen. The pharmacological basis of these effects of
buprenorphine (kappa-antagonism activity,mu-agonism activity) are discussed.

Publication Types:
Clinical Trial
Controlled Clinical Trial
English Abstract
Research Support, Non-U.S. Gov't

PMID: 11042867 [PubMed - indexed for MEDLINE]

4: Am J Psychiatry. 1987 Oct;144(10):1340-2.

Antipsychotic effect of buprenorphine in schizophrenia.

Schmauss C, Yassouridis A, Emrich HM.

Max Planck Institute for Psychiatry, Munich.

The antipsychotic potency of the partial opiate agonist buprenorphine was
evaluated in 10 neuroleptic-free schizophrenic patients suffering from frequent
hallucinations, delusions, and severe formal thought disorders. Buprenorphine
had a pronounced antipsychotic effect, which lasted about 4 hours, in patients
with schizophreniform disorders (N = 4) and paranoid schizophrenia (N = 3).

Publication Types:
Clinical Trial
Research Support, Non-U.S. Gov't

PMID: 3310672 [PubMed - indexed for MEDLINE]

1: Emrich HM, Gunther R, Dose M. Current perspectives in the pharmacopsychiatry of depression and mania. Neuropharmacology. 1983 Mar;22(3 Spec No):385-8. Review.

2: Emrich HM, Vogt P, Herz A, Kissling W. Antidepressant effects of buprenorphine. Lancet. 1982 Sep 25;2(8300):709. No abstract available.

3: Emrich HM, Vogt P, Herz A. Possible antidepressive effects of opioids: action of buprenorphine. Ann N Y Acad Sci. 1982;398:108-12. Original paper available.

4: Gold MS, Pottash AC, Sweeney D, Martin D, Extein I. Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence. Ann N Y Acad Sci. 1982;398:140-50.

5: Hesse M. The Beck Depression Inventory in patients undergoing opiate agonist maintenance treatment. Br J Clin Psychol. 2006 Sep;45(Pt 3):417- 25. PMID: 17147106 6: Gerra G, Leonardi C, D'Amore A, Strepparola G, Fagetti R, Assi C, Zaimovic A, Lucchini A. Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study. Prog Neuropsychopharmacol Biol Psychiatry. 2006 Mar;30(2):265-72. Epub 2005 Nov 23.

7: Ross J, Teesson M, Darke S, Lynskey M, Ali R, Ritter A, Cooke R. The characteristics of heroin users entering treatment: findings from the Australian treatment outcome study (ATOS). Drug Alcohol Rev. 2005 Sep;24(5):411-8.
8: Darke S, Hetherington K, Ross J, Lynskey M, Teesson M. Non-injecting routes of administration among entrants to three treatment modalities for heroin dependence. Drug Alcohol Rev. 2004 Jun;23(2):177-83.

9: Kosten T, Falcioni J, Oliveto A, Feingold A. Depression predicts higher rates of heroin use on desipramine with buprenorphine than with methadone. Am J Addict. 2004 Mar-Apr;13(2):191- 201.

10: Schottenfeld RS, Pakes JR, Kosten TR. Prognostic factors in Buprenorphine- versus methadone-maintained patients. J Nerv Ment Dis. 1998 Jan;186(1):35-43.

11: Callaway E. Buprenorphine for depression: the un-adoptable orphan. Biol Psychiatry. 1996 Jun 15;39(12):989-90. No abstract available.

12: Bodkin JA, Zornberg GL, Lukas SE, Cole JO. Buprenorphine treatment of refractory depression. J Clin Psychopharmacol. 1995 Feb;15(1): 49- 57.

13: Torrens M, San L, Cami J. Buprenorphine versus heroin dependence: comparison of toxicologic and psychopathologic characteristics. Am J Psychiatry. 1993 May;150(5):822-4.

14: Kosten TR, Morgan C, Kosten TA. Depressive symptoms during buprenorphine treatment of opioid abusers. J Subst Abuse Treat. 1990;7(1): 51- 4.
1: Neuropharmacology. 1983 Mar;22(3 Spec No):385-8. Current perspectives in the pharmacopsychiatry of depression and mania. Emrich HM, Gunther R, Dose M.

The observation that opiates and endorphins exert euphorogenic effects in normal probands points to a possible involvement of endorphins in different types of affective disorders. There are several powerful arguments that the activation of particular central opiate receptors (e.g. by "opium cure", beta-endorphin, partial agonists, release of endorphins via electroconvulsion) exerts curative effects in endogenous depression. Results from a double-blind investigation of the possible antidepressant action of the opiate partial agonist buprenorphine in patients with endogenous depression revealed a strong antidepressant effect of this substance. A series of anticonvulsants, possibly acting via a GABA-ergic- like mechanism (valproate, dipropylacetamide, carbamazepine and oxcarbazepine), have recently been shown by different groups to possess antimanic and also, partially, antidepressant properties. Furthermore, a synergistic mode of action in the prophylaxis of manic episodes has been observed as concerns valproate and lithium. On the other hand, there is some evidence from both in vitro and in vivo animal experiments that chronic application of lithium results in a modification of the GABA-turnover. The present paper reviews the present state of knowledge concerning the concept of a GABA-dependent regulation of affective states.

2: Lancet. 1982 Sep 25;2(8300):709. Antidepressant effects of buprenorphine. Emrich HM, Vogt P, Herz A, Kissling W.

3: Ann N Y Acad Sci. 1982;398:108-12. Possible antidepressive effects of opioids: action of buprenorphine. Emrich HM, Vogt P, Herz A.

4: Ann N Y Acad Sci. 1982;398:140-50. Antimanic, antidepressant, and antipanic effects of opiates: clinical, neuroanatomical, and biochemical evidence. Gold MS, Pottash AC, Sweeney D, Martin D, Extein I.

These clinical data may offer some support for the hypothesis that opiates have antidepressant, antimanic, and antipanic effects. This hypothesis should be studied directly by double-blind studies of the effects of exogenous and synthetic endogenous opioid peptides in patients with major depressive illness, panic and anxiety states, schizophrenia, and schizo-affective illness. These clinical data support our studies in nonhuman primates and man which suggest a common LC or NE hyperactivity may underly both drug withdrawal and spontaneous panic states. Whether endorphin deficiency or derangements account for the postulated NE hyperactivity needs additional study and we will discuss our preliminary work later. Failure of endorphins to terminate bursts in LC firing rate and NE release may be responsible for both of these types of panic states. In addicts, this mechanism could exist prior to opiate use, or abuse of potent exogenous endorphinomentic compound may cause an endorphin-abnormality. Both of these possibilities would be compensated by continuous opiate maintenance. Methadone maintenance is a complicated psychiatric, psychological, and social phenomenon. Further studies are necessary to evaluate the role of opiate maintenance in treating or suppressing the emergence of underlying psychopathology. Previous psychiatric hospitalization or treatment for a schizophrenic or affective illness may contraindicate absolutely the use of clonidine or other rapid detoxification methods. These data suggest the possibility of substituting a nonaddicting psychotropic medication for opiates in some patients who are self-medicators. The clinical data support other data suggesting the potential antipsychotic, antidepressant, and antianxiety/antipanic effects of the endogenous opioids, endorphins, and exogenous opioids, endorphins, and exogenous opiates. These and other data suggest potential utility for opioid agonists and endorphin testing in psychiatric treatment and diagnosis.

5: Br J Clin Psychol. 2006 Sep;45(Pt 3):417-25. The Beck Depression Inventory in patients undergoing opiate agonist maintenance treatment. Hesse M.

Centre for Alcohol and Drug Research, Aarhus University, Copenhagen, Denmark. mortenhesse@crf.dk

BACKGROUND AND OBJECTIVES: The Beck Depression Inventory (BDI) is a widely used measure of depression severity in both research and clinical contexts. This study aimed at assessing its stability and associations with ongoing drug use in a sample of patients in opiate agonist maintenance treatment who were not abstinent from illicit drugs. DESIGN AND METHOD: The study was a prospective, naturalistic study. Subjects in enhanced or standard psychosocial services along with opiate agonist maintenance treatment were administered the BDI and the European Addiction Severity Index (EuropASI) twice by research technicians, approximately 2 weeks after intake and at 18 months follow-up. FINDINGS: There were rather small mean changes from intake to follow-up in the BDI, and mean-level stability in subjects was rather high as evidenced by a high intra-class correlation between intake score and follow-up score. The stability of the BDI was reduced at high levels of drug use severity at intake, and BDI was a moderate predictor of drug use severity at follow-up. CONCLUSIONS: The BDI measures a construct that is both stable and of predictive validity in a sample of non-abstinent opiate agonist maintenance patients, although very severe drug use at baseline appeared to reduce the stability of the BDI.

6: Prog Neuropsychopharmacol Biol Psychiatry. 2006 Mar;30(2):265-72. Epub 2005 Nov 23. Buprenorphine treatment outcome in dually diagnosed heroin dependent patients: A retrospective study. Gerra G, Leonardi C, D'Amore A, Strepparola G, Fagetti R, Assi C, Zaimovic A, Lucchini A.

Addiction Treatment Centre, AUSL Parma, Italy. g.gerra@palazzochigi.it

The present study compared retrospectively in a clinical non-experimental setting the efficacy of buprenorphine (BUP) in different subgroups of dually diagnosed and non-dually diagnosed opioid-dependent patients: all the subjects included in the study showed severe long-lasting heroin addiction and 68.4% were affected by psychiatric comorbidity. Participants (206) (mean age 32.2+/- 8.9, 177 males-29 females) were applicants to a long-term buprenorphine treatment program (mean doses 7.9+/-0.42 mg). Aim of the study was to evaluate dual diagnosis variables possibly influencing retention rate and abstinence from illicit drugs. The patients were divided into 5 subgroups on the basis of dual diagnosis: group 1: major depression (MD) 29.61%; group 2: generalized anxiety (GAD) (11.2%); group 3: personality disorders (PD), antisocial-borderline (21.84%); group 4: schizophrenia (SC)(6.3%); group 5: substance use disorder without overt psychiatric comorbidity (SUD) (31.1%). Group 1 patients affected by MD showed the highest retention rate at 12 months (72.1%) in comparison with the other groups of patients: group 2 GAD (39.1%), group 3 PD (17.8%), group 4 SC (7.7%) and group 5 SUD, without comorbidity (45.3%) (p=0.006, p<0.001, p<0.001, p=0.002). Similarly, at 12 months, the patients affected by MD showed less risk of illicit opioid use (16.4%) than those affected by GAD (34.8%), PD (42.2%), SC (53.8%) and SUD without comorbidity (34.4%) (p=0.06, p=0.003, p=0.008, p=0.017). When evaluated on the whole sample, retention rate was not influenced by dose. In contrast, the higher BUP doses were associated with less risk of illicit opioid use, than lower doses (p<0.001). Multivariate analysis and factor analysis showed a greater association of outcome measures (retention rate and negative urines rate) with comorbid diagnosis (depression) (respectively 0.64) than with buprenorphine doses (respectively 0.54). Our data need to be interpreted with caution because of the retrospective methodology applied to a clinical non-experimental setting. BUP seems to be more effective in opioid-dependent patients affected by depression, probably due to the kappa opioid-receptors antagonist action, counteracting dysphoria, negativism and anxiety. High doses of BUP appear to predict a better outcome, in terms of negative urines, but not in terms of retention.

7: Drug Alcohol Rev. 2005 Sep;24(5):411-8. The characteristics of heroin users entering treatment: findings from the Australian treatment outcome study (ATOS). Ross J, Teesson M, Darke S, Lynskey M, Ali R, Ritter A, Cooke R.

National Drug and Alcohol Research Centre, University of New South Wales, Australia.

The current study aimed to describe the characteristics (demographics, drug use, mental and physical health) of entrants to treatment for heroin dependence in three treatment modalities; and to compare these characteristics with heroin users not in or seeking treatment. Participants were 825 current heroin users recruited from Sydney, Adelaide and Melbourne: 277 entering methadone/buprenorphine maintenance treatment (MT), 288 entering detoxification (DTX), 180 entering drug-free residential rehabilitation (RR) and 80 not in treatment (NT). Treatment entrants were generally long-term heroin users with previous treatment experience. The majority of the sample (55%) were criminally active in the month preceding interview. Injection-related health problems (74%) and a history of heroin overdose (58%) were commonly reported. There were high degrees of psychiatric co-morbidity, with 49% reporting severe psychological distress, 28% having current major depression, 37% having attempted suicide and 42% having a lifetime history of post-traumatic stress disorder. Personality disorders were also prevalent, with 72% meeting criteria for antisocial personality disorder and 47% screening positive for borderline personality disorder. Striking similarities were noted between the non-treatment and treatment groups in length of heroin use career, drug use and treatment histories.

8: Drug Alcohol Rev. 2004 Jun;23(2):177-83. Non-injecting routes of administration among entrants to three treatment modalities for heroin dependence. Darke S, Hetherington K, Ross J, Lynskey M, Teesson M.

National Drug and Alcohol Research Centre, University of New South Wales, Australia. s.darke@unsw.edu.au

A sample of 535 entrants to opioid dependence treatments across three treatment modalities were administered a structured interview to ascertain the prevalence of non-injecting heroin use. Ten per cent of participants had used heroin primarily by smoking/inhaling in the month preceding interview, and 9% had used heroin and other drugs exclusively by non-injecting routes. Non-injectors were younger (25.3 vs. 29.5 years), had higher levels of education (10.6 vs. 10.0 years), were more likely to be employed (33 vs. 18%) and had lower levels of recent crime (31 vs. 56%). They also had shorter heroin using careers (5.1 vs. 9.9 years), fewer symptoms of dependence (5.1 vs. 5.6), had been enrolled in fewer previous treatment episodes (3.3 vs. 11.5) and had less extensive lifetime (8.0 vs. 9.1 drug classes) and recent (3.6 vs. 4.9) polydrug use. Non-injectors were substantially less likely to report lifetime (13% vs. 58%) or recent (2% vs. 29%) heroin overdoses. There were no differences between the general physical and psychological health of the two groups. While non-injectors had a lower level of post-traumatic stress disorder (29% vs. 34%), there were no differences in levels of major depression, attempted suicide, antisocial personality disorder, or borderline personality disorder. A substantial minority of Australian treatment entrants are now using heroin exclusively by non-injecting routes. While this group is younger, and has substantially reduced risk of overdose and blood borne virus transmission, the physical and psychological health of non-injectors mirrors that of injectors.

9: Am J Addict. 2004 Mar-Apr;13(2):191- 201. Depression predicts higher rates of heroin use on desipramine with buprenorphine than with methadone. Kosten T, Falcioni J, Oliveto A, Feingold A.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA. thomas.kosten@yale.edu

The effect of lifetime depression was examined in a randomized clinical trial in 164 opioid- and cocaine-dependent patients who were treated with desipramine in combination with either methadone or buprenorphine. We examined treatment retention, illicit opioid and cocaine use, and depressive symptoms, and found that opioid-free urines at baseline, but not later in treatment, were greater among the depressed than non-depressed patients. Among the depressed patients, depressive symptoms at baseline, but not later in treatment, were greater in patients treated with buprenorphine than methadone. Desipramine did not reduce depressive symptoms more than placebo. Finally, the depressed patients treated with desipramine and buprenorphine showed the least improvement in opioid-free urines, while the non-depressed patients treated with desipramine and methadone had more opioid-free urines than those patients treated with placebo desipramine. Cocaine-free urines showed no association with depression. This poor outcome with desipramine and buprenorphine suggests that this medication combination is not indicated in depressed opioid-dependent patients.

10: J Nerv Ment Dis. 1998 Jan;186(1):35-43. Prognostic factors in Buprenorphine- versus methadone-maintained patients. Schottenfeld RS, Pakes JR, Kosten TR.

Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.

This study a) compared the effects of buprenorphine versus methadone maintenance on benzodiazepine and alcohol use and b) evaluated the prognostic significance of gender and psychopathology and their interaction with maintenance treatment. Eighty male and 36 female patients were randomly assigned to daily sublingual buprenorphine (4 or 12 mg) or oral methadone (20 or 65 mg). Maintenance medication was not associated with significant differences in alcohol or benzodiazepine use. Rates of abstinence from illicit opioids were significantly higher for females, within the buprenorphine 4-mg group, females also had significantly better retention, lower rates of opioid-positive urine samples, and higher rates of abstinence from illicit opioids. Lifetime sedative dependence was associated with significantly better retention, decreased rates of cocaine-positive urine samples, and increased rates of cocaine abstinence; among buprenorphine- but not methadone-maintained patients, it was also associated with increased rates of abstinence from illicit opioids.

11: Biol Psychiatry. 1996 Jun 15;39(12):989-90. Buprenorphine for depression: the un-adoptable orphan. Callaway E.

12: J Clin Psychopharmacol. 1995 Feb;15(1): 49- 57. Buprenorphine treatment of refractory depression. Bodkin JA, Zornberg GL, Lukas SE, Cole JO.

McLean Hospital, Consolidated Department of Psychiatry, Harvard Medical School, Belmont, MA 02178, USA.

Opiates were used to treat major depression until the mid-1950s. The advent of opioids with mixed agonist-antagonist or partial agonist activity, with reduced dependence and abuse liabilities, has made possible the reevaluation of opioids for this indication. This is of potential importance for the population of depressed patients who are unresponsive to or intolerant of conventional antidepressant agents. Ten subjects with treatment-refractory, unipolar, nonpsychotic, major depression were treated with the opioid partial agonist buprenorphine in an open-label study. Three subjects were unable to tolerate more than two doses because of side effects including malaise, nausea, and dysphoria. The remaining seven completed 4 to 6 weeks of treatment and as a group showed clinically striking improvement in both subjective and objective measures of depression. Much of this improvement was observed by the end of 1 week of treatment and persisted throughout the trial. Four subjects achieved complete remission of symptoms by the end of the trial (Hamilton Rating Scale for Depression scores < or = 6), two were moderately improved, and one deteriorated. These findings suggest a possible role for buprenorphine in treating refractory depression.
Buprenorphine versus heroin dependence: comparison of toxicologic and psychopathologic characteristics.

13: Am J Psychiatry. 1993 May;150(5):822-4. Buprenorphine versus heroin dependence: comparison of toxicologic and psychopathologic characteristics. Torrens M, San L, Cami J.

Substance Abuse Treatment Unit, Hospital del Mar, Barcelona, Spain.

Sociodemographic, toxicologic, and psychopathologic characteristics of 22 buprenorphine addicts and 45 heroin addicts admitted for inpatient detoxification were compared. Although the buprenorphine addicts were older, clinically significant differences were not apparent. The availability of buprenorphine may be the main reason for its abuse.

14: J Subst Abuse Treat. 1990;7(1):51-4. Depressive symptoms during buprenorphine treatment of opioid abusers. Kosten TR, Morgan C, Kosten TA.

Department of Psychiatry, Yale University School of Medicine, New Haven, CT.

Among 40 opioid addicts treated as outpatients with sublingual buprenorphine (2-8 mg daily) for a month, depressive symptoms significantly decreased in the 19 who were depressed at intake to treatment.

POSSIBLE ANTIDEPRESSIVE EFFECTS OF OPIOIDS:
ACTION OF BUPRENORPHINE
in K. Verebey (Ed.) Opioids in Mental Illness.
Ann N Y Acad Sci. 1982;398:108-12.

H. M. Emrich, P. Vogt and A. Herz
Max-Planck Institute for Psychiatry
D-8000 Munich 40, Federal Republic of Germany

ANTIDEPRESSIVE WIRKUNG VON OPIOIDEN ??
Introduction
Abbildung
Methods
Results
Discussion
References

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The euphorogenic and anxiolytic properties of opiates [1] and of endorphins [2] prompt questions as to the possibility that a defectively operating endorphinergic system may represent a causative factor in the pathogenesis of endogenous depression. Though from biochemical and pharmacological data the evidence in support of this hypothesis is weak (cf. rd. [3]), it nevertheless, requires additional evaluation. However, irrespective of the presence of a hypotectical constitutional deficit of endogenous morphinomimetic substances compensated for by an exogenous supply in the therapy of depressed patients, the question arises if, independently from such a possible type of metabolic dysfunction in depression, there may exist direct pharmacodynamic therapeutic effects of opioids in depressive syndromes. Since anxiety and sleep disturbances, in addition to melancholia, make up an integral part of the psychopathology of depression, from their profile of action, it may be anticipated that opioids could be highly effective, therapeutically, in depressive iliness.

Indeed, since die time of Emil Kraepelin [4] the "opium cure" has been recommended for the treatment of depressed patients, employing slowly increasing and later decreasing dosages of tinctura opii [5] and of other opiates [6]. Interestingly, according to reports of that time, although a standardized evaluation of the therapeutic efficacy was, and is, lacking, this treatment was effective and did not result in opiate addiction, possibly, since the doses applied were comparatively low. Later, Fink et al. [7] applied the mixed agonist/antagonist cyclazocine (1.0 -3.0 mg) in 10 severely depressed patients and observed a strong antidepressive effect, in particular concerning the items "depressed mood" and "apathy." A further clinical evaluation of possible beneficial effects of opiates has been deferred, possibly owing to the psychotomimetic effects of cyclazocine and, furthermore, in view of the fact that the discovery of tricyclic antidepressants and of MAO-inhibitors opened a new era in the pharmacotherapy of depressive syndromes. Interestingly, immediately after the discovery of the endorphins, which shed new light onto the possible psychotropic effects of an activation of opiate receptors, new attempts were initiated in the evaluation of the possible antidepressive effects of opioids. Klare et al. [2] were the first to perform clinical trials in different types of psychiatric disorders ( schizophrenia, depression, neuroses) by use of ß-endorphin infusions (1.5-6.0 mg) and observed in two depressed patients, in an open design, positive effects of this treatment. Angst et al. [8], also in an open triel, investigated the possible antidepressive action of infusions of 10 mg of ß-endorphin and detected a switch to hypomania / mania in three of six depressed patients. Subsequently, double- blind trials as to the possible antidepressant efficacy of ß-endorphin have been performed by two groups [9, 10]. Gerner et al. [9] reported a significant improvement 2 to 4 hours after ß-endorphin infusions, as compared to placebo treatment in 10 depressed patients, wheras Pickar et al. [10] found no significant change in 4 depressed patients after ß-endorphin therapy. The application of the synthetic enkephalin analogue FK 33-824 in 10 depressed patients produced a sizable improvement in 3 of the patients and a tranquilizing effect in 4 of them [11].
Interestingly, the investigation as to the possible value of opioids in antidepressive therapy were not confined to endogenous morphinomimetic substances or their derivatives but were - in line with the attempts performed prior to the studies of Fink et al. [7] - also undertaken with opiates such as morphine and other opium alkaloids in clinical therapeutic trials. Gold et al. [12], for example, presented data suggestive of a potential antidepressant and anxiolytic / antipanic effects of opiates. On the other hand, Extein et al. [13], reported only a slight antidepressive effect of 5.0 mg morphine in 10 patients with major depressive disorders (open study), whereas a double-blind investigation in 6 depressed in-patients, 5.0 mg methadone proved not different in effect from placebo.

Another basis front which to speculate as to possible antidepressive properties of opioids lies in the fact that electroconvulsion, which is certainly one of the most efficacious and rapidly acting somatic treatments in depression, possesses endorphin-activating properties. As shown by Belenky and Holaday [14] in animal experiments. electroconvulsion induces a spectrum of vegetative, naloxone-reversible changes, which apparently reflect an EC-effected activation of particular endorphinergic systems. Similar conclusions may be derived from the estimation of plasma ß-endorphin immunoreactivity in depressed patients before and after
electroconvulsion, which exhibits a highly significant increase after this procedure [15]. Interestingly, there endorphin-mobilizing properties are no confined to electroconvulsion but also are exhibited by other physical methods used in the past in the treatment of psychotic disorders (e.g. cold-water stress[16], insulin coma [17], rotational stress [cf, ref. 18]. Additionally, the stressful procedure of hemodialysis, which in some cases apparently exerts antidepressant effects [19], unequivocally induces an elevation of plasma ß-endorphin immunoreactivity [20], an effect which is possibly also exhibited by sham-dialysis. Therefore, some of the controversial results concerning the action of hemodialysis in different types of psychoses may be explained in terms of an nonspecific stress effect of this procedure.

Investigations as to a possible antidepressant effect of the opiate mixed agonist / antagonist buprenorphine [21] are suggested not only by the total body of evidence concerning the possible antidepressive effect of opioids, reviewed above, but also by the observations that it, as shown by Mello and Mendelson [22] has highly positive subjective effects in opiate addicts. Furthermore the finding that buprenorphine has mood-improving effects in postoperative patients and the very important fact that this strong analgesic substance is devoid of psychotomimic effects and has a very low abuse potential [24, 25] suggests the performance of clinical trials with the aim of developing a new opioid substance with a strong antidepressant potency and a high degree of drug safety.

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The study was performed by use of a double-bind A1/B/A2-design (A1/2= placebo; B = buprenorphine). Ten patients who met the research diagnostic criteria [26] for major depressivedisorder gave their informed consent to participate in the study. The duration of the three therapeutic phases varied between: A,: 1-7 days, B: 5-8 days; A2: 0-4 days. The patients were free of conventional thymoleptic drugs. Before the beginning of the trial, a wash-out period of 4 days was performed. During the buprenorphine treatment phase, two sublingual tablets (0.2 mg per day) were given at 8:30 and 16:30 h. Psychopathological evaluation was performed by a trained psychiatrist every two days in the afternoon by use of the IMPS [27] and the Hamilton scale for depression [28]. Additionally, the global impression of depression and, as a screening of side effects, the Symptoms "nausea," "vomiting," "dizziness," and "euphoria" were evaluated by use of the VHS ( Verlaufs-Beurteilungs-Skala).'

The mean results of the Hamilton-scores before (A1), during (B1; B2; B3) and after (A2) buprenorphine treatment are depicted in FIGURE 1.

FIGURE 1.. Averaged Harnilton-Scores of 10 depressed patients before (A1), during (B1-B3), and after (A2) buprenorphine treatment. Bars: SEM; for details see text.

The data B1-B3 represent the average values of the Hamilton-score at the beginning of the blind buprenorphine treatment (B1), in the middle of buprenorpine treatment phase (B2), and at e end of buprenorphine treatment (B3). A2 represents the average data of the Hamilton-scores at the end of the second placebo treatment period. As can be seen in FIGURE 1, there is a strong reduction in the Hamilton-scores during the phases B1 - B3 in comparison with the placebo phases A1 and, to a lesser degree, also in comparison with the second placebo phase A2. These differences are highly significant (p≤ 0.02, Wilcoxon-test).

An evaluation of the single data of individual patients (data not shown) reveals that about 50% of the patients responded very strongly to buprenorphine, whereas the other 50% were, apparently, nonresponders. Since practically all of the patients included in the study were nonresponders to conventional thymoleptic therapy, this is a significant result. Most of the patients experienced some degree of slight nausea, dizziness and sedation (vomiting in one case) in the course of the study, but these side effects, with the exception of the one case of vomiting, never became a problem during therapy.

As shown in the present investigation, the mixed opiate agonist/antagonist buprenorphine exhibits antidepressant properties in cases not responding to conventional thymoleptic therapy. This is a remarkable finding, since for this type of patient, an inevitable consequence would be the application of electroconvulsion, a somatic type of therapy which, in view of some of its side effects [30] and therapeutic risks [31] is not a desirable choice in the treatment of psychiatric patients. Therefore, the intriguing possibility has to be considered that the type of therapy indicated here may represent a way of mimicking by chemical means the neurobiologically therapeutic effects of electroconvulsion; one can thus speculate that other physical and/or chemical means of inducing endorphin activation (e.g. inhibition of enkephalinases) may, also, in the future, play a therapeutic role in the treatment of endogenous depression.

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