Bernard P ROQUES et Florence NOBLE
Departement de Pharmacochinue Moleculaire et Structurale, U266 INSERM, UMR 8600 CNRS, Universite Rene Descartes,
4 Avenue de l'Observatoire, 75270 Pans Cedex 06

The use of mice with invalidation of genes encoding endogenous neuropeptides (pre-proenkephalm for example) or various types of G-protem-coupled receptors (mu- , delta- opioids, dopamme D2, cannabmoid CB1 ) or DA reuptake protein was of great value to investigate the role of these different targets in drug addiction (1, 2, 3) Moreover numerous factors participate to the vulnerability in the transition from dmg abuse to addiction In almost all cases, this was related to difficulties in the abilities to carry out adaptational behaviours to face up to stress situations This could result in a permanent anhedonia, temporarily overcommed by drugs consumption and might be due to a defect in the endogenous rewarding system strictly controlled by endogenous opioids (4) Such a defect could have genetic basis or could reflect the presence of associated psychiatric disorders (co-morbidity) the origin of which may be found in conflicting experiences during the early childhood It is well-known that these early stress situations severly increase (by a factor ten) the risk of drug abuse during teenage years From a neurochemical point of view it has been demonstrated using various animal models and behavioural experiments, as well as biological experiments including measurement of endogenous effector by microdialysis (DA, opioids, cholecystokmme, CCK) that hcits (alcohol, tobacco) as well as illicits (heroin, cocain, amphetamines, cannabinoids ) produce a sensation of well-being by activating the dopammergic mesolimbic system through different mechanisms direct stimulation of DA neurons of the VTA or inhibition of DA or 5HT (with ecstasy) reuptake in the N ace In all cases this leads to an increase in the level of DA in this brain structure (5-7) Nevertheless, there is no direct relationship between the amounts of DA in N Ace synapses and drug abuse This indicates that drug abuse eventually following by addiction, is due to several events, and particularly the association between reward and emotional state surrounding the drug consumption This seems to generate i) an hypersensitivity of the DA system , 11) a mnesic consolidation of this association, resulting in a compulsive search of rewarding substance

References

1 Matthes H W, Maldonado, R Simonm, F Valverde, 0 , Slowe, S , Kitchen, I, Befort, K , Diench, A , Le Meur, M Dolle P Tzavara, E , Hanoune, J , Roques, B P and Kieffer, B L Nature, 383, 819 823, 1996

2 Maldonado, R , Saiardi, A , Valverde, 0 , Samad, TA , Roques, B P and Borreh, E Nature, 388, 586-589, 1997

3 Ledent,C Valverde, 0 Cossu G Petitet F Aubert, J F Beslot F Bohme GA Imperato, A , Pedrazzmi T Roques, B P, Vassart, G , Fratta, W & Parmentier, M Science, 283 401-404 1999

4 0 Bnen, C P Opioid addiction In Herz A Akil H Simon E J eds Handbook of Pharmacology Opioids II Sponger Verlag, Berlin, 803 823, 1993

5 Kahvas, PW, Richardson-Carlson, R and Orden, V Biol Psychiatry, 21, 939 950, 1986

6 Roques, B P, Noble, F, Dauge V Fourme Zaiuski, M C and Beaumont A Pharmacol Rev 45,87 146 1993

7 DiChiara.G Eur J Pharmacol, 375 13-30 1999

PATIENT ACCEPTABILITY OF TRANSDERMAL FENTANYL (DUROGESICO) VERSUS SUSTAINED RELEASE MORPHINE IN THE TREATMENT OF CHRONIC NON-MALIGNANT PAIN MANAGED IN THE COMMUNITY - INTERIM DATA

Martin Johnson for the FEN GBR 21 GP Study Group
Ashville Medical Centre Bamsley S Yorkshire S703RJ UK

Aim of investigation: Despite widespread prescribing of strong opioids for pain in the community there is little controlled clinical trial data in this arena Sustained release preparations offer greater convenience improved compliance and, once stabilised overall less patient management time than immediate release preparations This study set out to investigate the patient acceptability of Durogesic (fentanyl transdermal system) compared to sustained release morphine (SRM) in subjects requiring continuous treatment with strong opioids for chronic non malignant pain

Methods: There will be up to 300 patients whose pain is being managed by their General Practitioner recruited m to this 13-month, open-label study To date, 215 strong opioid naive patients have been randomised to either Durogesic patches or SRM tablets Starting doses (Durogesic 25ug/hr every 72hr or SRM 15-30mg every 12hr) are adjusted by increments of Durogesic 25ug/hr every 72hr and SRM 30 50% after 12hr to achieve adequate pain control Patients are seen up to 5 times during the first month and monthly thereafter to assess acceptability of treatment (side effects pain control rescue medication taken ease/convenience of use) bowel function sleep quality and pattern and to assess treatment overall

Results: An interim analysis on the first 100 patients entered into the study will be presented This will include data on patient demographics side effects and withdrawals from the study

Acknowledgements: Study supported by Janssen Cilag Ltd

INTRAVENTRICULAR OPIOID TREATEATMENT IN CHRONIC PAIN

E. Waidhauser
Neurochirurgie, Paracelsus Klinik, 49076 Osnabruck, Germany

The intraventricular route of opioid administration was choosen in a small group of 18 patients because all other treatments failed. 6 of them even had intrathekal opioid treatment before. All patients underwent test trials with externalized catheters. For long term treatment a drug infusion pump was implanted.

Morphine was the opioid drug of first choice. Only in cases of unacceptable side-effects buprenorphme or fentanyl were given. The average dose was 7 mg morphine per day.

Best results were observed in patients with failed back surgery syndrome in spite of previous intrathecal treatment.

TRAMADOL IN THE TREATMENT OF TENSION HEADACHE: A CONTROLLED TRIAL VS PLACEBO

G. Sandrini. G. Nappi, G. Bussone, L. Grazzi, F. Puca, S. Genco, E. Stemieri, A. Pim
'Centre Interuniversitario Studio Cefalee, Istituto Neurologico C. Mondino, PV, Centro Cefalee, Istituto Neurologico C. Besta, MI; Servizio Cefalee di Interesse Neurologico, Policlinico, BA;
Centro per lo Studio delle Cefalee, Policlinico, MO

Aim of investigation: the trial was conducted in four Italian headache centres to compare the activity of tramadol in patients with a diagnosis of tension headache according to the IHS classification.

Methods: thirty-seven patients (11 male, 26 female), mean (SD) age 33.1 ± 10.8 years were treated with tramadol or placebo with 20 drops that should be repeated every 30 minutes in the first 2 h if pain relief was insufficient. A double blind cross-over, experimental design was employed. Each patient had to treat six successive tension headache attacks (three pairs), with a 48-hour wash out between one attack and the next.

Results: the clinical evaluation was performed on 41 complete pairs of attacks in 23 patients. Tramadol limited the seventy of the attacks in 41% of patients at 2 h, compared to 19.4% with placebo (p=0.0171) and the number of tension headache attacks resolved within 2 h was reached by more patients taking tramadol than placebo (16 vs 6). During the trial 14 patients treated with tramadol complained adverse events, mainly dizziness, pruntus and vomiting.

Conclusions: tramadol in this first controlled trial in patients with tension headache showed better analgesic action than placebo. To support these results should be performed additional trials in a larger study population.

Acknowledgements: Medical Department, Formenti - Grünenthal (Italy)

THE OUTCOME OF LONG-TERM OPIOID THERAPY IN CHRONIC NON -CANCER PAIN

J.Lejcko, S. Machart, H. Minarova, N. Popperova, M. Bflek, E. Kasal, I. Chytra, Anaesthesiology and Intensive care Dept-Pain Centre, Quality of Care Dept, Charles Univ Hospital, Pilsen., Anaesthesiology and Intensive Care Dept-Pain Clinic, Hospital Ceske Budejovice., Czech Republic

Aim of investigation: Evaluation of the efficacy and safety of long-term strong opioid therapy in chronic non-cancer pain. Comparison of use of fentanyl TTS (Durogesic) and morphine SR (MST Continus).

Methods: Retrospective analysis of data from 48 patients treated with opioids in 1999 was performed. Previous treatment had been included. Fentanyl-TTS (group I.) was used in 28 patinets (11 males, 17 females, mean age of 59, mean treatment duration 105 days, pain origin-3 neuropathic, 14 nociceptive, 11 mixed), 19 patients (group II.) were given morphine SR (11 males, 8 females, mean age of 51, mean treatment duration 154 days, pain origin-4 neuropathic, 7 nociceptive, 8 mixed). Issues of potential benefit-pain relief (assessed by VAS 0-100 at base line and at the end of follow-up), daily life activities (DLA, 3-point scale), treatment acceptability (3-point scale), and potential risk opioid side effects were monitored.

Wilcoxon and Man-Whitney tests were used for VAS evaluation, data are shown as medians and 95% confidence intervals for median.

Results: There was no dose escalation (median 25u/h) in group I. VAS at baseline 40-100, median 70, VAS at the end of follow-up 10-80, median 40, DLA median 2, acceptability median 2. Adverse effects: 3 x vomiting, 5 x constipation, 1 x pruritus, 9 x sedation..

Dose escalation in group II. was recorded in the range of 30 to 60mg/day, VAS 60-100, median 80 before morphine, VAS at the end of follow-up 10-90, median 60, DLA - median 1, acceptability median 1, adverse effects: 2 x vomiting, 5 x constipation, 2 x pruritus, 4 x sedation.

Conclusions: In both groups we proved essential pain relief (Wilcoxon test) and correlation between acceptability and DLA improvement. However, no statistically significant differences between the two groups (Man-Whitney test) in terms of pain relief and side effects occurence were found. In conclusion, long-term opioid therapy, when standard treatment has failed, can be useful for chronic non-cancer pain patients

Pain in Europe III. EFIC 2000, Nice, France, September 26-29, 2000. Abstracts book, p. 62, 289, 308, 314.