EFFECTS OF THE NOVEL ANALGESIC COMPOUND OT-7100 ON HYPERALGESIA IN ANIMAL MODELS OF ACUTE AND PERIPHERAL NEUROPATHIC PAIN

Tsuneo Yasuda*. Takeshi Iwamoto*, Shinya Miki*, Norihiro Yoshinaga*, Seiji Sato*, Hideaki Kohri*, Koichi Noguchi², Emiko Senba³ Otsuka Pharmaceutical Factory, Inc. Naruto, Tokushima, 772-8601. Hyogo College of Medicine, Nishmomia, Hyogo, 663-8501. Wakayama Medical College, Wakayama City, Wakayama, 641-6012, Japan.

Aim of Investigation: To investigate the effects of OT-7100 on prostaglandin E₂ (PGE₂) biosynthesis in vitro, as well as on acute hyperalgesia induced by yeast and substance P in rats, and on hy-peralgesia in a rat chronic constriction injury model to the sciatic nerve (Bennett model) which represents a model for peripheral neuropathic pain.

Methods: PGE₂ biosynthesis by cyclooxygenase was measured in the preparation from sheep seminal vesicles. The nociceptive thresholds were determined by the Randall-Selitto method when hyperalgesia was induced by yeast and substance P in rats, and by the Randall-Selitto and Plantar Test methods in the Bennett model.

Results: OT-7100 did not inhibit PGE; biosynthesis at concentrations of 10^-8-10^-4M. Single oral doses of OT-7100 (3-10 mg/kg or 0.1-3 mg/kg) were effective on the hyperalgesia induced by yeast or the hyperalgesia induced by substance P on which indomethacin had no effect. Repeated oral administration of OT-7100 (10 and 30 mg/kg) was effective in normalizing the mechanical nociceptive threshold in the injured paw without affecting the nociceptive threshold in the uninjured paw in the Bennett model. The differences in withdrawal latency to noxious heat stimuli between injured paw and uninjured paw were also decreased by OT-7100 (10 and 30 mg/kg) in the Bennett model.

Conclusion: These results suggest that OT-7100 is a new type of analgesic with the ability to normalize the nociceptive threshold in peripheral neuropathic hyperalgesia.

THE INCIDENCE OF ADVERSE EFFECTS WITH THE USE OF "BURST" KETAMINE: A PROSPECTIVE AUDIT

Michael Ashby, Kate Jackson. Peter Martin*, Michelle White*. McCulloch House, Monash Medical Centre, and Dept of Medicine, Monash Univ, Clayton, Victoria 3168, Australia

Aims of the Investigation: In addition to determining efficacy (see abstract - Can "Burst" Ketamine Wind Down Wind Up) the incidence of adverse effects during a short term viz 3 day infusion of an effective dose ofketamine administered as a continuous subcutaneous infusion (CSCI) against refractory cancer pain was determined.

Methods: 20 patients from June to December 1998 Ketamine was given by a dedicated Graseby MS26 syringe driver (with water as the dilutent) to a maximal dose of500mg/24hrs. Additional documentation included specific inquiry and note of any psycho-mimetic sequelae, twice daily pulse and Blood Pressure recordings and infusion site redness or infection plus frequency of site changes were recorded.

Results: 15/20 patients achieved good pain relief. 2 patients described "feeling a bit spaced out" but elected to continue the effective treatment. One patient, who had also reacted adversely to morphine and fentanyl, developed an acute brain syndrome which resolved rapidly after cessation. A fourth patient with severe anxiety and agitation pre-infusion was withdrawn after 24 hours as unsuitable. P + BP remained within 10% of pre-infusion levels in all patients. No increase in local site toxicity was noted as corn pared with concurrent infusions or the unit's usual experience with CSCI.

Conclusions: The incidence of serious adverse effects was low. Additionally our audit fails to support the exclusion of patients in whom significant hypertension or tachycardia would be dangerous, eg unstable angina or history ofhaemorrhagic stroke. Significant injection site toxicity was not observed.

THE EFFECTS OF ORAL AMANTADINE IN THE TREATMENT OF NEUROPATHIC PAIN

Sei Fukui. Yasuo Komoda*, Yoshihisa Fujino, Atumi lida*, Shuichi Nosaka*, Dept ofAnesthesiology, Shiga Univ of Medical Science, Otsu, Shiga, 520-2192, Japan

Aim of Investigation: NMDA receptors are involved in the development of neuropathic pain.

Amantadine is clinically used for the management ofParkinson's disease, and has recently shown to be an NMDA receptor antagonist. The aim of this study was designed to investigate the efficacy of oral administration ofamantadine in relieving neuropathic pain.

Methods: Fifteen patients with neuropathic pain resistant to conventional pain treatment (post-herpetic neuralgia: 10, post-thoracotomy pain: 2, phantom limb pain:!, brachial plexus avulsion pain:!, CRPS type-1: 1) were studied. In order to select patients with NMDA receptor antagonist sensitive pain, we conducted a double blind test with low-dose ketamine. 4 weeks following oral administration ofamantadine 200mg/day, spontaneous pain intensity was assessed by visual analogue scale (VAS) and allodynic area were measured.

Results: More than 50% pain reliefer almost complete marked reduction of mechanical allodynia were obtained in 3 patients (20%). One patient obtained excellent pain relief but caused intolerable side effect 3 months following the treatment. 10 patients (67%) caused no improvement in pain control. Side effect were observed in 6 patients (40%: dry mouth; 3, excitation;!, involuntary movement, dyskinesia;!, hallucination;], drowsiness;!). Conclusion: The present results were far less promising and suggested that oral administration ofamantadine may reduce some forms of neuropathic pain but the clinical use may be reduced because of the frequency of intolerable side effects. Ketamine test did not predict the effect ofamantadine.

LONG-TERM EFFICACY OF ORAL KETAMINE FOR CHRONIC PAIN PATIENTS

Asako Furuhashi*. Hiroki lida, Shuji Dohi, Tomoo Takeda*, To-shio Asano*, Tokushige Tanahashi, Tatsuya Tujito*, Dept of Anesthesiology and CCM, Gifu Univ School of Medicine, Gifu 500-8705,Japan

Aim of Investigation: Ketamine has a noticeable analgesic action with NMDA receptor blocking property and can be used for the treatment of various acute and chronic pain. We previously reported that oral ketamine could produce good pain relief for patients with neuropathic pain(l). However, there is no information about long-term efficacy and side effects. In the present study we assessed the safety of oral ketamine and development of tolerance in four patients treated by oral ketamine longer than 6 months.

Methods: We studied in four patients (aged 27-60yr) with neuropathic pain (patients ofpostamputation stump pain, reflex sympathetic dystrophy, tongue neuralgia, and post-thoracotomy pain). All subjects have been treated by oral ketamine (25-200mg/day) longer than 6 months. Side effects, activity of daily life, and changes in dosage of oral ketamine and other analgesics were evaluated. Pain scores were rated by a visual analog scale (100mm VAS).

Results The patients had oral ketamine therapy for 21 months (6-48 months) on the average and reported on reducing VAS score from 60 (45-72) to 28 (11-44) mm Hallucination was observed in one patient (postamputation stump pain) but it disappeared after reduced dosage of oral ketamine (200mg to 1 OOmg/day) No other side effects such as neurologic and blood chemistry abnormalities were observed Any patient did not require increase of dosage of oral ketamine Moreover two patients could reduce the dosage of oral ketamine (from 200mg to lOOmg and from lOOmg to 25mg) At present all subjects were able to return to their Jobs Conclusion Oral ketamine is effective for patients with neuro-pathic pain without remarkable side effects, and tolerance to ketamine is unlikely to occur even if it has been used longer than 6 months

Reference (1) Anesthesiology 85, A797, 1996

CAN "BURST" KETAMINE WIND DOWN WIND-UP: PROSPECTIVE AUDIT

Kate Jackson. Michael Ashby, Peter Martin*, Michelle White* McCulloch House, Monash Medical Centre, and Dept of Medicine, Monash Univ, Clayton, Victoria 3168, Australia

Aims of the Investigation A prospective audit of the "burst" use of the NMDA antagonist Ketamine, i e short term viz 3 days, of an effective dose of Ketamine administered as a continuous subcutaneous infusion against refractory cancer pain

Methods Patients of a palliative care service from June to December Pain mechanisms, 4 hourly verbal response scores (VRS) (0-10), specific inquiries for any psycho-mimetic sequelae, all medications including opioid breakthroughs, and the duration of any response were recorded Ketamine was started at 100mg/24hrs and increased daily, if required, to 300mg then 500mg until an effective dose or 500mg was reached This dose was then continued for 3 days and then ceased Response criteria were 50% or greater reduction in mean VRS, 50% or greater reduction in opioid requirements (either 24hr dose and/or number of breakthroughs) and/or significantly improved functional status A patient was deemed to have responded if they fulfilled at least two of the three criteria

Results 20 patients were admitted, 15 responded In 13 the response was maintained after ketamine was ceased In 2 pain recurred and ketamine was restarted and maintained till death Maximum doses for the responders were lOOmg in 5, 300mg in 4 and 500mg in 6 patients The predominant pain mechanisms were (responders/total) mucositis 2/2 other somatic 4/4, visceral 0/1 and neuropathic 9/13 Psycho-mimetic sequelae were significant in only 1 patient - a responder

Conclusions This audit suggests that burst Ketamine can indeed wind down wind-up and should be tnaled against all refractory cancer pain, not solely neuropathic pain

FURTHER EVIDENCES OF CYP2D6 DEPENDENT DEXTROMETHORPHAN ANTINOCICEPTIVE EFFECT

M Kondo Oestreicher*. J Desmeules, V Piguet, & P Dayer, Multidisciplmary Pain Center, Clinical Pharmacology, Univ Hospital CH-1211 Geneva 14 Switzerland.

Aim of Investigation: Dextromethorphan (DEM) is extensively metabolized into dextrorphan (DOR) by the liver polymorphic isozyme CYP2D6 In vitro DEM and DOR are N-Methyl-D-Aspartate (NMDA) antagonists Single oral doses of DEM reduced spontaneous pain and increased R-III threshold ofelectncally elicited pain in CYP2D6 poor metabolizers only (Desmeules, JPET, 288, 607, 1999) We therefore investigated the antmociceptive effect of multiple DEM oral doses in extensive metabolizers (EM)

Methods and Results In a randomized double-blind crossover and placebo (P) controlled study in CYP2D6 EM healthy volunteers the effects of DEM (50 mg slow release, 50 and 100 mg standard for-mulation/6h) were assessed Antmociception was monitored for 36h by objective (R-III reflex) and subjective pain threshold monitoring (Viking IV, Nicolet, Madison) After 50 or 100 mg of rapid release formulation, DEM produced a sustained analgesic effect whereas the slow release formulation did not differ from P

Conclusion DEM also exerts an analgesic effect in EM subjects These results confirm that in man analgesic effect is mainly mediated by the unchanged DEM despite the higher potency of DOR NMDA blockade in vitro

DEXTROMETHORPHAN DOES NOT AFFECT MORPHINE ANALGESIA IN ISCHEMIC PAIN IN HEALTHY VOLUNTEERS

Aida Plesan. Marta Segerdahl, AlfSollevi, Dept of Anaesthesia, Huddmge Univ Hospital, S-141 86 Huddmge, Sweden

Aims of the Study NMDA-receptor activation is known to play an important role in vanous pain states NMDA- receptor antagonists have therefore been extensively studied as possible adjuvants or alternatives to opioid therapy Dextromethorphan (DEX) has been found to be a weak non-competitive NMDA-receptor antagonist This study evaluates the effect of two doses of DEX in combination with morphine (MO) in experimental ischemic pain

Methods After IRB approval, 20 fast-metabolising healthy volunteers were included in a double blind, randomised, placebo-controlled, cross-over study A run-in experiment was done prior to randomisation Six experiments were carried out at least 1 week apart Oral DEX (30 or 90 mg) or placebo was administered 1 hour prior to test IV MO (0,1 mg/kg) was given dunng 10 mm just prior to test Pain (VAS 0-100) was assessed every minute during 30 mm of ischemic forearm tourniquet test (1) VAS values were calculated to sums of pain scores (SPS) which were analysed by Fned-man's ANOVA and Wilcoxon's signed rank test Results MO reduced SPS compared to placebo (p<0,01) None of the DEX doses reduced SPS and DEX combined with MO did not influence the analgesic effect of MO

Conclusion The study shows that the weak NMDA- receptor antagonist DEX does not affect opioid analgesia in the current experimental pain model Previous data have reported DEX to enhance MO analgesia in oral surgery patients (2) Therefore, DEX interaction with opioid analgesia requires further evaluation in different pain modalities

References 1) Anesth Analg 79 787-791, 2) Clin Pharm Ther 63 pp 139A,1998

Acknowledgments Supported by the Swedish Medical Research Council proj no 7485, Karolmska Inst and Astra Pain Control AB

PAIN CONTROL BY CHOCOLATE FLAVORED KETAMINE TABLET

Atsushi Uehira*. Munehiro Taniguch*, Akira Tanaka², Shinnya Hon*³, Yuichi Ishibe*³, Toru Sato*³, Taniguchi Hospital, Pain Clinic Dept, 1-13-1 Agei, Kurayosi city, Totton, 682-0021, Japan, Geriatric Health Services Facility "Hamayu", Nakamachi, Tottori city, 680-0016, Japan, Totton Univ, Faculty of Medicine, Dept of Anesthesiology & Reanimation 36-1 Nishicho, Yonago, Totton, 683-0826,Japan

Aim of Investigation Ketamine has been used orally for controlling pain Since ketamine is usually available in injectable liquid forms and tastes very bitter, it shall be too difficult for patients to handle Then we have made chocolate-flavored ketamine (Ketamine Chocolate) tablets

Methods 1) Preparation of Ketamine Chocolate tablets 50g of chocolate is melted in a microwave oven, 20ml ofketaral50* (1 gram ofketamme, Park Davice Co, Ltd ) is added, heat it again until it becomes pasty Then, the thick paste is equally divided into 64 pieces, each of which is formed to a small tablet, containing approx 15mg ketamine 2) A double-blind test using Ketamine Chocolate tablets and placebo chocolate tablets in CRPS patients 3) A clinical comparative study between Ketamine Chocolate tablet and small dose im ketamine, in 33 pain patients with PHN, HZ or cancer pain

Results 1) The taste ofKetamine Chocolate tablets is acceptable They are administered orally with no prbolem 2) Ketamme Chocolate tablets were found effective to relieve pain in 12/13cases, whereas the placebo tablets were in 5/12 (p<0 01)3) Sub-lingual ketamine Chocolate tablets decreased VAS from 43 4± 19 1 to 20 8± 14 1 (p<0 01), and 5mg ofim ketamine decreased from 42 9± 15 8 to 170±14 1(p<001) No significant difference was found between both

Conclusions Our Ketamine Chocolate tablet has high patient's compliance and yet powerful pain relief as much as that of 5mg of ketamine mtra-muscular administration They shall be beneficial to many patients who suffer from intolerable pain such as of CRPS, PHN, HZ and cancer

GABAPENTIN IN THE TREATMENT OF PAIN AFTER TRAUMATIC AVULSION OF THE BRACHIAL PLEXUS AND IN PHANTOM LIMB PAIN AFTER LEG AMPUTATION AT THE HIP JOINT

M.V Ribera.G Espmosa*, C Barutell, Pain Clinic Unit, Vail d'Hebron Hospitals, Barcelona, Spain

Aim of Investigation To present the results obtained with Gabap-entin in the treatment of patients with phantom limb pain and in patients with pain after avulsion of the brachial

Methods The total number of patients treated was 11 6 with phantom limb pain after amputation of the leg at the level of the hip joint (group I), and 5 with traumatic avulsion of the brachial plexus (group II) We have revised the mean time elapsed from the appearance of symptoms until being visited, concomitant treatment, maximal dose achieved with Gabapentin and the maintenance dose, and also appearance of side effects

Results In group I (range of age between 15-36 years) time elapsed to the visit was 0-10 days In 3 patients we collocated a pendural catheter before surgery to control pain, and in one patient we started Gabapentin as first treatment also before surgery Maximal dose achieved was 800-2000 mg/d and maintenance dose was 400-1200 mg/d Two patients left Gabapentin because of the disappearance of symptoms Side effects were seen in one patient (drowsiness) In group II (age between 20-44 years) time until being visited was 2days-20years Maximal dose was 1200-2000 mg/d, and maintenance dose was 1200 mg/d No side effects were seen Concomitant treatment in both groups was NSAID, anticon-vulsants, antidepressants drugs and other opioids Pain was released in all patients

Conclusions Gabapentin is effective in the treatment of pain associated with phantom limb after amputation and traumatic avulsion of brachial plexus

STUDY OF GABAPENTIN USE FOR CHRONIC PAIN MANAGEMENT IN A VETERAN POPULATION

Jean CD*, Rey JA . Hart A *, Miami Veterans Affairs Medical Center, 1201 NW 16^th Ave , Miami, FL 33125, USA

Aim of Investigation To evaluate the effectiveness ofgabapentm in pain management Objectives include 1) evaluate patient-rated pain scales, 2) determine dosage regimen associated with pain relief, 3) report adverse effects from gabapentin use

Methods: Seventy-four patients who received gabapentin for chronic pain management as of September 1997 were evaluated Data collection included patient demographics, pain diagnosis, dosage regimen, gabapentm-specific analgesic response, patient-rated pain scores (0-10 scale), adverse effects and concomitant psychotropic or analgesic medications

Results Twenty-seven of the 74 patients were excluded from the efficacy aspect of the study because of a predetermined inadequate length of treatment (<2 months) Chronic pain-related diagnoses included neuropathies, enthesopathies, radiculopathies and lami-nectomies Pain rating scales from 43 patients indicate that gabapentin use resulted in statistically significant (paired t-test, p<0 01) mean reductions in pain of 19% for "worst experienced pain" and 37% for "pain at best" Overall 60% of patients reported reductions in "worst" pain and 74% reported reductions in their "best" pain rating scores Of the 36 patients that specifically reported a descriptive response to gabapentin, 75% (n=27) reported pain relief (p<0 01) and 25% (n=9) reported no pain relief A majority of these responders (77%) reported an analgesic response within 2 months of therapy Mean daily dose was 1663 mg/day (r=200-3600 mg/day) Adverse effects were reported by 21 of the 74 patients who received gabapentin therapy Conclusions Gabapentin may have beneficial effects in a variety of pain syndromes Further controlled research is needed to fully determine gabapentin's role as an analgesic agent

CARBAMAZEPINE IN FABRY DISEASE

S V Kopishinskaya*. A V Gustov* (SPON V M Nazarov), Dept of Neurology, Regional Hospital, Rodionov St, 190, Nizhny Novgorod, 603126, Russia

Aim of Investigation To investigate the pain relief action ofcar-bamazepine (CZ) on Fabry patients suffering from episodic painful crises and acroparesthesias

Methods We observed five patients with FD and severe pain who received 200mg of carbamazepme twice a day for 3 months Results Two patients responded to carbamazepme with partial amelioration of their pain, two patients reported complete pain relief, and one patient had no benefit

Conclusions Fabry disease (FD) is an X-lmked glycosphmgolipid storage disease resulting from a deficiency oflysosomal alpha-galactosidase The main neurological manifestations of this neu-ropathy are episodic painful crises and constant acroparesthesias with burning discomfort in hands and feet The results show that CZ is a necessary drug for the treatment of painful crises and par-esthesias associated with FD

EFFICACY AND SAFETY OF GABAPENTIN IN DIFFERENT NEUROPATHIC PAIN SYNDROMES

Roberto Pisano. Annalisa Vacquer*, Maunzio Cocco*, Tonio Sol-lai*, Giovanni Manduco* Servizio Anestesia e Terapia Antalgica, Az Osp G Brotzu Via Peretti, 09134 Caglian, ITALY

Aim of Investigation To evaluate the efficacy and the safety of gabapentin, a new anticonvulsant recently available in Italy, in chronic neuropathic pain of central or peripheral origin

Methods Fifty consecutive patients, aged 28 to 88 years (mean age 61 86 years), suffering from neuropathic pain with a VAS (Visual Analogue Scale) of 7/10 or more, were included in the study Seventeen patients (34%) suffered from centra] neuropathic pain (1 cerebral post stroke, 2 multiple sclerosis, 6 traumatic myelopathy and 8 post-hcrpetic neuralgia) and 33 patients (66%) suffered from peripheral neuropathic pain (11 cervical and 3 lumbar radiculopa-thy, 3 stump pain, 3 brachial neuropathy, 6 neuritis, 7 post-surgery neuropathy, 10 trigcmindl neuralgia) Twenty-four patients had been previously treated with other anticonvulsant drugs (carbamazepme, phenytom, clonazepam, lamotngine) With their informed consent, all patients received gabapentin 300 to 900 mg/ddily during the first month, increased up to 1800 mg/daily if necessary Twenty-seven patients were also treated with an antidepressant drug The therapy's efficacy was appreciated with a 5-point verbal rating scale poor or ineffective, light, moderate, good, excellent

Results Four patients withdrew spontaneously from the study because of side effects or mefficacy and 46 completed the study Systematic evaluation was performed after 1 month and 4 months After the first month 7 patients (15 22%) out of 46 reported poor or no efficacy, 10 (21 74%) light, 16 (34 78%) moderate, 13 (28 26%) good, nobody referred excellent results After 4 months 3 patients (6 52%) had poor or no efficacy, 5(10 87%) light 8 (17 39%) moderate, 18 (39 13%) good, 12 (26 09%) excellent (Wilcoxon p < 0,05) Side effects such as drowsiness, dizziness, tremor and dyslalia appeared in 6 patients (13 04%) who completed the follow-up

Conclusions' These data show patients' improvement when the dosage was adjusted and therapy prolonged. The statistical evaluation didn't show any significant difference of subjective clinical efficacy between patients with centra] or peripheral neuropathic pain, in patients previously treated with other anticonvulsants and in patients with associated antidepressant therapy (Wilcoxon p > 0,05). Gabapentin appears to be effective on central and peripheral neuropathic pain with poor side effects.

A PLACEBO-CONTROLLED STUDY OF LAMO-TRIGINE IN THE TREATMENT OF DISTAL SENSORY POLYNEUROPATHY ASSOCIATED WITH HIV INFECTION

D Simpson*. J. McArthur²*. A. Khan*. J Godbold, Y Markanan, K Ebel-Frommer. SPON F Young), Dept of Clinical Neurophysiology, Mount Sinai Medical Center, New York, NY 10029, USA,² Dept of Neurology/Pathology, Johns Hopkms Univ Hospital, Baltimore, MD, 21205 USA

Aim of Investigation To investigate the analgesic efficacy ofla-motngine (LTG) in the treatment of painful HIV-associated distal sensory polyneuropathy (DSP) in a 14 week, multicenter, randomized, double-blind, placebo controlled clinical trial

Methods LTG was initiated at 25 mg per day and slowly titrated over 7 weeks to 300 mg per day. Change in pain as assessed utilizing the modified Gracely scale was the primary outcome measure, with secondary outcome measures including change in neurologic examination, use of concomitant analgesic medications, and global pain relief.

Results Of 42 enrolled subjects, 13 (11LTG/2PBO) did not reach maximal dose titration at week 7. Rash was the cause for dropout in 5 of the LTG subjects 20 of the remaining 29 evaluable subjects received placebo and 9 received LTG Baseline pain scores between the two groups were not significantly different (LTG 1 09 ± 0.32, Placebo 1 05 ± 0 33). LTG-treated subjects had a significantly greater reduction in average pain from baseline to week 14 (-0 55 ± 0 41) than did subjects in the placebo-treated group (-0 18 ±041, p=0 03), adjusting for baseline levels of pain Change in peak worst pain was not significantly different between the two groups

Conclusions LTG demonstrated efficacy in the treatment of pain associated with HIV DSP, in this study, confirming anecdotal reports of the efficacy of LTG in the treatment of painful neuropathy and tngeminal neuralgia Results in this small pilot study need to be confirmed in a larger controlled study

Acknowledgments Supported by a grant from Glaxo Wellcome, Inc

TOPIRAMATE, A NOVEL ANTIEPILEPTIC DRUG, IN NEUROPATHIC PAIN

Carolyne Timberlake. Sam Chong, Michelle Fung*. Thomas Smith*, Magdi Hanna. Pain Relief Unit, King's College Hospital, Denmark Hill, London, SE5 9RS, UK.

Aim of Investigation An open study looking at the analgesic efficacy oftopiramate, a novel antiepileptic drug, in neuropathic pain

Methods Adult patients with uncontrolled neuropathic pain of greater than 6 weeks duration fulfilling the inclusion and exclusion criteria were recruited for the study Following a detailed pain history, a Short-Form McGill Pain Questionnaire (SF-MPQ) was completed and the total SF-MPQ scores noted (max score =60) Patients were randomly allocated to three (a,b,c) treatment groups (Topiramate, (a) lOOmg/day X 9 weeks, (b) lOOmg/day X 3 weeks then 200mg/day X 6 weeks, (c) lOOmg/day X 3 weeks then 200mg/day X 3 weeks then 300mg/day X 3 weeks) and kept a daily pain diary. No other alteration was made to their pain management. Patients were reviewed at 3, 6 and 9 weeks on Topiramate noting side effects and completing the SF-MPQ at each visit

Results 12 patients have completed this on going study, with a mean age of 48 5 (Range 29-72) and median duration of pain of 42 months (6-180) At 3 weeks, 6 patients on topiramate had a highly significant reduction in their total median pain score from baseline (Median SF-MPQ Score 15 5 at 3 weeks, 28 85 baseline, p=0 0087), 2 patients had no improvement in their pain control and 4 patients had withdrawn due to adverse effects 5 patients continued on topiramate for the 9 week period, 4 reporting substantial improvement in their pain control at the end of the study and highly significant reductions in their total median pain scores from inclusion (14 at 9 weeks, 29 at inclusion p=0 0079). All patients reported side effects ofvanable severity, including somnolence, fatigue and concentration difficulties. These side effects resolved within 3-6 weeks but in 6 patients lead to their premature withdrawal from the study.

Conclusions Topiramate appears to be a highly effective analgesic in selected patients with neuropathic pain Unfortunately the use of this drug may be limited due to side effects

LAMOTRIGINE: A MORPHINE-SPARING DRUG FOR CENTRAL PAIN

M Van Bastelaere*. M De Laat (SPON J Devulder) and G Roily, Pain Clinic, Univ Hospital of Gent, 9000 Gent, Belgium

Aim of the investigation Evaluating pain relief using incremental doses oflamotngme in a patient with a benign spinal cord tumor no longer responding to a daily analgesic dose of 3800 mg oral morphine and 250 mg intravenous ketamme

Method. A 70-year-old male, diagnosed with a non curative epen-dymoma D4-D11 making him paraplegic and suffering intractable pain (VAS 10/10) in the back and both legs, could only be managed by 2800 mg oral morphine and 250 mg intravenous ketamme (VAS 2/10) Four months later, daily oral morphine was increased to 3800 mg Pain relief became insufficient (VAS 8/10) and the drugs made the patient very confused Oral lamotngme was gradually added to the opioid mixture hoping to decrease the opioid dose and to improve quality of life

Result After 3 months, the daily analgesic dose was reduced to 2200 mg oral morphine, 250 mg intravenous ketamme and 600 mg oral lamotngme. VAS dropped to 0/10 and confusion completely vanished

Conclusion. By adding lamotngme, we could improve analgesia (VAS 0/10), reduce the morphine consumption by 42% and improve quality of life by getting an alert patient In function of time we hope to decrease morphine consumption by increasing lamo-tngme dose

Acknowledgments We wish to thank the firms. GlaxoWellcome and Parke-Davis for providing their drugs in compassionate use

EFFECT OF ANTIDEPRESSANTS AND VALPROATE SODIUM ON NEUROSPECIFIC CURRENT PERCEPTION THRESHOLD

Akira Kudoh. Hironon Ishihara*, Akitomo Matsuki*, Dept of Anesthesiology, Univ. ofHirosaki School of Medicine, Hirosaki 036-8563,Japan

Aim of Investigation. We investigated sensory threshold of chronic depressed patients with antidepressant and epileptic patients with valproate sodium and patients with post herpetic neuralgia (PHN) with current perception threshold (CPT), which is reliable peripheral nerve integrity

Methods' We studied 20 control patients and 20 chronic depressed patients, 14 epileptic patients and 12 patients with PHN. CPTs were obtained at 2000Hz, 250Hz and 5Hz on the right ring finger of each patient using Neurometer 12 patients with PHN were given amitnptyline 60 mg/day and were done CPT test in 2 weeks, 1 month and 2 months after its administration

Results:

Ranges	Control pt	Depressed pt	Epileptic pt
2000Hz 250Hz 5Hz	198.9±5.8 62.0±8.9 35.3±5.8	190.8±19.2 76.1±11.3 78.2±12.7	350.6±61.3* 338.6±64.3* 193.2±21.1*

Data are expressed as mean ± SEM :p<0,05>, vs control pt.

2000 Hz, 250 Hz and 5 Hz stimulation ofCPTs in patients with PHN significantly increased to 323.5 ± 26.9, 149.6 ± 29.3 and 204.9 ± 29.3, respectively in 2 months after the administration.

Conclusion: For epileptic patients with valproate sodium, there were significant increase in thresholds at 2000 Hz, 250 Hz and 5 Hz stimulation. CPTs in chronic depressed patients were no significant increases in three stimulation frequencies. However, thresholds at 2000 Hz, 250 Hz and 5 Hz stimulation in patients with PHN given amitriptyline significantly increased in 2 months after the administration. Our result indicated that valproate sodium increases sensory threshold, leading to sensory disturbance. Amitriptyline also increases sensory threshold in short-term administration, however, long-term administration ofantidepressants has no effect on the sensory threshold.

PAROXETINE, A SELECTIVE SEROTONIN REUPTAKE INHIBITOR FOR NEUROPATHIC PAIN SYNDROMES

Anthony TaeHyung Han. M.D.. SungKyunKwan Univ College of Medicine, Samsung Medical Center, Pain Management Center, Seoul, 135-730, Korea

Aim in Investigation: Tricyclic antidepressants (TCA) have been used for multiple pain syndromes for their analgesic effects. They, however, often have anticholinergic side effects and therefore search for more selective drugs with fewer side effects is required. Paroxetine, a selective serotonin reuptake inhibitor devoid ofauto-nomic side effects, was evaluated for its role as an analgesic adjuvant in the management of various neuropathic pain.

Methods: Total 40 patients were divided equally into four groups as diabetic neuropathy, postherpetic neuralgia, central pain syndrome and cancer related brachial or lumbosacral plexopathy. Patients have been stabilized in their analgesic regimen at least four weeks prior to enrollment into study. TCA, if taken, was discontinued for two weeks for wash out period. Baseline five point verbal pain intensity score was obtained and oral administration ofpar-oxetine 20 mg was initiated as an out patient basis. At two weeks follow up visit, pain intensity scores, pain improvement scores, drug efficacy and tolerability, and overall evaluation were assessed. Use of other co-analgesics and incidence of side effects were also obtained.

Results: Pain intensity scores before treatment were ranged from severe to very severe. After two weeks of treatment with par-oxetine, these have improved to mild or moderate. These findings were objectively reflected in pain improvement scores. There are increasing number ofnonresponders as pain becomes severe, systemic and malignant. Drug efficacy, tolerability and overall evaluation were ranged from good to excellent. Incidences ofCNS, GI and anticholinergic side effects appear to be evenly distributed among the different groups with overall incidence of 27.5% altogether and spontaneously disappeared after discontinuation of medication.

Conclusions: Paroxetine, a selective serotonin reuptake inhibitor, appears to be universally effective as adjuvant analgesic for the management of various neuropathic pain syndromes. It demonstrates a tendency to lose its effectiveness as pain becomes more serious.

VENLAFAXINE USE IN THE TREATMENT OF 3 DIABETIC PERIPHERAL NEUROPATHY PAIN

Christine Kaminski-Price. Jose Rev. Steven Bowen*, Wendy ^fl Cruz*, Pat Estrep*, Nova Southeastern Univ College of Pharmacy i and the North Broward Hospital District Dept of Ambulatory • Services, Seventh Ave Family Health Center, 200 NW 7¹¹¹ Ave, Ft. Lauderdale,Fl,33311,USA

Aim of Investigation: To determine ifvenlafaxine 1) will reduce diabetic peripheral neuropathy pain, 2) worsen diabetic control, and 3) analgesic response correlates to an antidepressant response.

Methods: Diabetic patients with chart documented peripheral neuropathy were screened for enrollment. Assessments of pain, depression, anxiety and vital signs were conducted at baseline, weeks 1 -8, and 12 by the investigator. Assessments of fasting blood glucose, lipid profile and glycosolated hemoglobin were conducted at baseline, week eight and twelve.

Results: 20 of 31 patients enrolled completed the study. Using a numerical analog scale (0=no pain, 10=worse pain imaginable) significant improvements from baseline were seen at weeks 1-12 in patient rated pain scores (p<0.001) and clinical global impression scales for severity of pain (p<0.001). A 70%, 90%, & 90% response rate for CGI scales for improvement in pain (1=very much improved or 2=much improved) were seen at weeks 4, 8, & 12 respectively (p<0.01). All of these improvements occurred in patients who were depressed or not. There were no statistical differences from baseline in fasting plasma glucose, lipid profile, glycosolated hemoglobin, heart rate and weight. Interestingly, there were significant improvements in the lowering of blood pressure at weeks 3-12 compared to baseline (p<0.05).

Conclusions: Strong evidence of efficacy for diabetic peripheral neuropathy pain is not evident for all antidepressants and there are significant side effects that limit their use. Venlafaxine appears to be a good alternative for the treatment of diabetic peripheral neuropathy due to its positive response on pain without compromising diabetes control.

Acknowledgments: Wyeth-Ayerst Pharmaceutical Company sponsored drug costs.

OPEN-LABEL, DOSE ESCALATION TRIAL OF FLOCOR IN PATIENTS WITH SICKLE CELL DISEASE AND ACUTE CHEST SYNDROME

S K Ballas. B A Files*, L J Benjamin, S Wojtowicz-Praga* and M Grindel, Jefferson Medical College, East Carolina Univ, Albert Einstein College of Medicine, Theradex, and CytRx Corporation, USA

Aim of Investigation: FLOCOR (purified poloxamer 188) is a nonionic surfactant with rheological properties that improves blood flow by reducing viscosity and adhesive frictional forces. It has been shown to decrease duration of crisis, pain intensity and analgesic use in patients (pts) with sickle cell pain (Blood 90: 2041, 1997). This Phase I trial is designed to determine the safety of FLOCOR in acute chest syndrome (ACS).

Methods: FLOCOR is administered as a 200 mg/kg bolus over 1 hour followed by 40 or 60 mg/kg/hr for 23 hrs. Eligibility: sickle hemoglobinopathy, sudden onset of acute chest pain or respiratory distress for ^ 4 hours, new infiltrates on chest radiograph (CXR), ALT ^ 1,5x's normal, and normal renal function. Exclusions: Bleeding disorder, septicemia, drug/alcohol abuse, inadequate IV access, acute myocardial infarction, recent surgery, CVA, or receiving another investigational drug, with the exception ofhy-droxyurea.

Results: 12 of the 13 pts enrolled (7F, 5M, age range 4-39 years) received FLOCOR. Presenting symptoms included chest pain, fever, dyspnea, and tachypnea. Baseline CXR revealed > 2 lobes involved in 9 of the 10 readings available. Baseline hemoglobin ranged from 4.9-10.1 g/dl. Pharmacokinetics: peak (Ihr) 6/8 pts-0.26-0.71 mg/ml; steady-state (24hr) 7/8 pts-0.17-0.45 mg/ml. Hospital stay ranged from 4-14 days. The mean hospital stay for children was 8 6 days, and, for adults 8 0 days Pulse oximetry at discharge was 95-100%. One patient's CXR was normal by the end of FLOCOR infusion The remaining improved, including 3 total resolutions within 4-5 weeks No serious adverse events were detected Oxygenation normalized and CXR evidence of disease diminished A decrease in hospital days was accomplished compared to that previously reported

Conclusion FLOCOR appears to be relatively safe at 200/40 mg/kg/hr and 200/60 mg/kg/hr showing promise in the treatment of ACS Further dose escalation is in progress.

EXPERIENCES/INTERACTIONS WITH THE NMDA RECEPTOR

Helen Hays, Mary Ann Woodroffe. 604 College Plaza, 8215 - 112 St, Edmonton, Alberta, T6G 2C8, Canada

Aim of Investigation. In recent years, much research has been focused on the N-methyl-D-aspartate (NMDA) system and its involvement in pathological pain states Consequently, the use of NMDA antagonists may play an important role in the treatment of difficult pain syndromes. This poster presents our clinical experiences in using medications, specifically dextromethorphan (DM), ketamine, and methadone which act as blocking agents at the NMDA receptor

Methods. Adult out-patients are referred for the treatment of chronic pain When conventional methods are ineffective, opioids and analgesic adjuvants are mailed Follow-up is accomplished through frequent telephone calls, whereby medications are adjusted according to pain and side-effects Additionally physician appointments are regularly scheduled for assessment

Results Of these 3 medications, methadone, a mu-receptor opioid agonist known to have blocking action at the NMDA receptor, has been the most benefit in relieving chronic pain and also is the best tolerated agent In a double-blind placebo-controlled trial involving 9 patients, DM was ordered in doses of either 150 mg/day or 300 mg/day for 1 week Three patients reported decreased pain and 4 had no benefit Two patients discontinued the study due to side-effects Even those who experienced some pain relief did not continue to use DM due to the cost. Twenty-one patients were mailed on ketamine, in doses ranging from 40 - 500 mg day. Only 3 patients tolerated ketamine and experienced benefit Side-effects, such as the psychomimetic symptoms, were common and a major reason for discontinuing the drug

Conclusions DM and ketamine have the potential to relieve pain associated with neuropathic pain syndromes However, problematic side-effects and cost may hinder their clinical use Methadone is better tolerated and can be very beneficial in relieving chronic severe neuropathic pain

MARIJUANA FOR THE MANAGEMENT OF PROXIMAL MYOTONIC MYOPATHY

Helen Hays. Mary Ann Woodroffe, 604 College Plaza, 8215 - 112 St, Edmonton, Alberta, T6G 2C8, Canada

Aim of Investigation The debate on the legalization of marijuana for medicinal purposes continues in Canada and the United States Marijuana has been reported to be effective in controlling nausea and vomiting associated with cancer chemotherapy and acquired immunodeficiency syndrome (AIDS), glaucoma, stimulating appetite, relieving symptoms ofneurologic and movement disorders, and treating pain We report an interesting case study of a 31 year old man with proximal myotonic myopathy (PROMM) who experienced dramatic relief of muscle weakness and dysesthesias with the use of marijuana

Methods This patient agreed to undergo specific myometry testing to determine the efficacy oftetrahydrocannabinol (THC), the most active ingredient in marijuana After stopping marijuana for a period of 6 days, a physiatnst performed a physical examination and muscle testing in all four limbs On the same day, a physiotherapist completed a myometer reading exam to determine muscle strength and she was blinded to the results of the physiatnst. These tests were repeated 4 days later after marijuana was re-instituted, the patient has a consistent supply and smokes 0.5 gm reefers, 3-4 times daily

Results. Improved function was demonstrated in all muscles. Grai 5 strength was noted in all muscle groups in the lower extremities normal strength was achieved even in areas where he was grade 3 on initial testing Relief of dysesthetic pain was also reported

Conclusions Marijuana has been effective in treating this patient with PROMM, whereas numerous trials of analgesics, including opioids, and adjuvant medications were either ineffective or not tolerated due to side-effects Additional research is needed to determine the long-term benefits and risks of marijuana usage for specific medical problems

SUBSTANCE P ANTAGONISM IN FIBROMYALGIA: A TRIAL WITH CJ-11,974

Brucc H Littman , Frances A. Newton , and 1. Jon Russell. Pfizel Central Research, Groton, CT 06340, USA, and The Univ ofTex, Health Science Center, San Antonio, TX 78284-7868 USA

Aim of Investigation This double-blind, placebo-controlled, randomized, eight week crossover study was conducted to evaluate treatment offibromyalgia (FMS) with a neurokinin-1 (NK-1) receptor antagonist, CJ-11,974 NK-1 receptors are specific for substance P (SP), SP is a major mediator of pain, and SP is elevated i the spinal fluid of FMS patients.

Methods Thirty subjects with active, pnmary FMS (1990 ACR criteria) were randomized to receive either 50 mg BID ofCJ-11,974 or an identical-appearing placebo capsule BID for four weeks, followed by crossover to four weeks of treatment with the alternative. Investigator variables sum (TPI) of tenderness sevenf (0-4 scale) at each of 18 defined points, average pain threshold (APT) from dolonmetry scores, and global severity (0-10) Patien self-assessment variables' VAS (0-31 points) for sleep quality, pain, morning stiffness, and hand/foot dysesthesias For each efficacy measure, the value after four weeks of CJ-11,974 treatment was compared with the value after placebo and significance was determined by a 2-tailed, paired t-test

Results Twenty-seven subjects completed, one was lost to follow up, and two discontinued early None of the investigator-derived variables were significantly affected by CJ-11,974 Patient measures, shown as Mean ± SEM

	Sleep	Pain	Disesth.	AM Stiff.
Placebo	21 6± 1 5	21 6± 1 6	182±1 7	3 1±09
CJ11974	20 8 ± 1 6	20 1 ± 1 6	146±17	23±04
p-value	0.63	0.35	0.03	0.38

Despite the lack of quantitative significance, 48.1%, 51 6% and 44.4% of subjects had better scores after CJ-11,974 while only 25 9%, 29 6% and 25 9% had better scores after placebo for sleep quality, pain and morning stiffness respectively Dysesthesia improved significantly CJ-11,974 was generally well-tolerated

Conclusions Blockade of NK-1 receptors did not eliminate their pain but significantly improved dysesthesia NK-1 blockade may prove therapeutically useful in FMS

Acknowledgment' Grant-Pfizer Central Research

EFFICACY OF TIZANIDINE IN NEUROPATHIC PAIN: AN OPEN-LABEL STUDY

Manlyn Semenchuk. Scott Sherman, Neurology Clinic, Univ of Arizona Medical Center, Tucson, Arizona 85719

Aim of Investigation To assess the efficacy and tolerability of tizanidine in neuropathic pain

Methods In an open-label study, 20 patients with neuropathic pain received 4 mg once daily for 7 days, followed by weekly dose escalation of 4 mg to his/her maximum tolerated dose or a maximum of 36 mg over an eight week period Treatment effects were assessed by daily ratings of pain intensity, post-treatment global ratings of pain relief, and daily ratings of side effects

Results Results will be presented during the meeting following completion of full statistical analyses Preliminary results indicate that patients receiving tizanidme report their pain relief is improved or much improved following doses of 8 mg or greater per day (range 8 mg to 36 mg daily) The average pain score prior to tiza-nidine was 6 4, which decreased to 3 3 in the patients who improved The majority of side effects were rated as mild and consisted primarily of fatigue, dry mouth, weakness and dizziness These symptoms had a tendency to recede with continuation of therapy

Conclusions. Chronic neuropathic pain can be challenging to treat, medications are the most important part of management We conclude that tizanidme may be an effective treatment for neuropathic pain in many patients and is well tolerated, offenng an alternative for patients unable to tolerate other medications Inhibition of the synaptic transmission ofnociceptive stimuli in the spinal pathways may mediate this effect Placebo-controlled trials oftizanidine for the treatment of neuropathic pain should be considered, and mechanistic information should be sought in comparative trials with alternative agents such as tncyclic antidepressants and anti-convulsants

Acknowledgments Supported in part by a grant from Elan Phar-maceuticals

THE EFFECT OF ORAL AMANTADINE IN CHRONIC PAIN PATIENTS WITH POSITIVE KETAMINE CHALLENGE TEST

Manami Takano. Yoshito Takano, Isao Sato, Dept ofAnesthesiol-ogy, Koshigaya Hospital, Dokkyo Univ, School of Medicine, Ko-shigaya, Saitama, 343-8555 Japan

Aim of Investigation Recently, drug challenge test has been prevailing to decide what drug should be chosen for the treatment of neuropathic pain. Among them, ketamme-test predicts the involvement ofNMDA receptor In the present study, we examined the effect of oral amantadme, which is low-affinity, non-competitive NMDA receptor antagonist in central and peripheral neuropathic pain patients

Methods Eight chronic pain patients who showed positive ketamme-test suffenng from PHN (number ofpatient(s), 1) traumatic cervical radiculopathy (1), degenerative cervical radiculopathy (1), central post-stroke pain (2), lumbar discopathy (1), diabetic neu-ropathy (1), or failed back surgery syndrome (1) were given oral amantadme, 50-150 mg/day Pain score (PS) [no pain = 0, pain before taking amantadme = 10] was evaluated one month after the start ofamantadme administration All patients suffered for more than 6 months and receiving antidepressants and neural blockade, which failed to alleviate pain Informed consent has been obtained from all patients.

Results. In all patients, amantadme reduced PS (PS 0-2,2 cases, PS 3-5, 2 cases, PS 6-9, 4 cases) Seven patients experienced improved feeling of depression Three patients complained slight dizziness

Conclusions In neuropathic pain patients, who tested positive in ketamme-test, oral amantadme was effective to alleviate pain and improved the quality of life. Amantadme reportedly lowers psy-chotomimetic properties when compared to other non-competitive NMDA receptor antagonist such as PCP or ketamme These results suggest that oral daily administration ofamantadme can be a choice for neuropathic pain patients who are resistant to conventional therapies

THE NMDA-ANTAGONIST MEMANTINE INCREASES PAIN THRESHOLD IN HEALTHY VOLUNTEERS

M Tegenthoff. K Witscher*, P Schwenkreis*, R Dertwmkel²*, M Zenz², J -P Malm*, Dept of Neurology, Dept of Anaesthesiol-ogy, Ruhr-LJniv Bochum, BG-K-lmiken Bergmannsheil, 44789 Bochum, Germany

Aim of Investigation From animal studies there is evidence for an important role of the NMDA receptor in central pain processing Other NMDA antagonists like ketamme are known to have potent analgetic properties, but not much is known about the analgetic properties of the NMDA antagonist memantme We investigated the effect ofmemantme on pain threshold in healthy volunteers

Methods 8 healthy right-handed volunteers received memantme or placebo in a randomized double-blind crossover study design Duration of drug intake was 8 days, with incrementing dosage ofme-mantme up to 30mg in the memantme session At day 8, thresholds for aversion, pain, intervention and pain tolerance were measured after electrical stimulation of the skin (lOOHz, 0,1ms) and exposure to an iced water bath (4°C) Memantme plasma levels were determined in each session as well The interval between memantme and placebo session in each subject measured at least 14 days Thresholds with and without memantme intake were compared Additionally, a psychological questionnaire was performed in order to control the influence of affective factors

Results Under both conditions (iced water bath and electncal stimulation), an increase of pain thresholds under memantme medication could be seen in the healthy volunteers when comparing memantme with placebo session

Conclusions Our results show that the NMDA-antagonist meman-tme is able to increase pain threshold in healthy volunteers, indicating analgetic properties of the drug However, psychotropic side-effects of the drug must be taken into account Further investigations are needed to evaluate the potential usefulness ofmeman-tme in patients with different kinds of pain

Acknowledgments The study was supported by Hauptverband der Berufsgenossenschaften, St Augustm (Germany)

PRELIMINARY RESULTS OF EFFICACY & SAFETY STUDY OF CORDOX™ (FRUCTOSE-1,6 DlPHOSPHATE) FOR THE TREATMENT OF ACUTE PAINFUL EPISODES OF SICKLE CELL DISEASE

Zofia E Dziewanowska*. Ewa Karwatowska Prokopczuk, Paul J Marangos, Cypros Pharmaceutical Corp , Carlsbad, CA, Anthony W Fox, E B D Group, Carlsbad, CA, David Green, Northwestern Univ-RIC, Chicago, IL, Wendell Ross, Duke Univ of Medical Ctr Durham, NC, Martin Stemberg, Univ of Mississippi, Jackson, MS, Brian Adier, Univ of Alabama, Birmingham, AL, Mabel Koshy, Univ of Illinois, Chicago, IL, Troy Guthne, Univ of Florida, Jacksonville, FL (SPON Carlton Dampier)

Aim of Investigation The purpose of this trial was to evaluate the potential therapeutic benefit of Fructose-1,6-diophosphate (Cordox™) a naturally occurring intermediate ofglycolytic pathway which has a variety of beneficial effects on ischemic tissue and blood elements

Methods This was a pilot, randomized, multi-center, double-blind, placebo-controlled study to evaluate the safety and efficacy of intravenous infusion of either 50, 100 or 250 mg/kg of Cordox™ or placebo in over 46 adult patients with Sickle Cell Disease (SS) during acute painful episode The patients were concurrently treated with parenteral narcotic analgesics (PNA)

Results The results showed that 50 mg/kg cohort statistically significantly reduced pain intensity as compared to placebo The onset of action was rapid (1 hour) Cordox™ was well tolerated and the only drug-related changes were a transient, dose-related increase in serum phosphate and an occasional decrease in serum calcium

Conclusions We conclude that, since Cordox™ is not an analgesic drug, its efficacy likely reflects the amelioration of several ischemic and inflammatory aspects of the crisis These encouraging results warrant taking this molecule into larger, definitive efficacy trials

Acknowledgments Employees at Cypros Pharmaceutical Corp , 2714 Loker Ave West, Carlsbad, CA 92008 and the co-authors who are Clinical Investigators in this trial

TOPICAL LIDOCAINE PATCH RELIEVES A VARIETY OF PERIPHERAL NEUROPATHIC PAINS: AN OPEN LABEL EXPERIENCE

Bradley S Galer, Allison Devers. Russell Portenoy, Ken Cubert, Craig Shalmi, Dept of Pain Medicine & Palliative Care, Beth Israel Medical Center, New York, NY -USA

Aim of Investigation Controlled clinical trials have established that topical lidocaine patch (TLP) is effective and safe for posther-petic neuralgia To define other peripheral neuropathic pain syndromes that may benefit from TLP, an open-label longitudinal study was performed

Methods. 16 patients with pain refractory to systemic opioid and non-opioid analgesics were given a trial of TLP TLP was cut to fit the painful region, administered 12 hrs on/off, and used ^ 1 week All patients were asked to rate the degree of pain relief obtained from TLP (^ 1 week), a verbal pain relief scale (PRS) was administered - [0-worse pain, 1- no change, 2- slight relief, 3- moderate relief, 4- a lot of relief, 5- complete relief]

Results 15/16 (94%) reported pain relief, with 13/16(81%) moderate or greater pain relief TLP was used for a mean of 6 weeks with continued relief No side-effects were reported

Diagnosis Post-thoracotomy (n=1) CRPS-I (n=5) Stump (n=l) Intercost neuralgia (n=1) Neuroma (n=3) Myalg paresthetica (n=2) Polyneuropathy (n=2) Post-mastectomy (n=1)

PRS 5 4/4/3/3/3 4 3 4/3/2 5/3 1/3 2

Conclusions: The depth of cutaneous analgesia increases with application time of EMLA. Biopsy punch insertions are acceptable to depths of 1-2 mm after 60 mm, 2-3 mm after 120 mm and 6 mm after 3-4 hours. Punch insertions seem relevant for assessing depth of analgesia.

RELATIONSHIP BETWEEN PAIN DECREASE AND OEDEMA REDUCTION AFTER ACUTE ANKLE SPRAIN - A FIRST PHARMACODYNAMIC APPROACH OF NSAID'S TOPICAL TREATMENT

M.G. Germ and J H Insuasty (SPON E Boccard), Clinical Research Dpt - Laboratoires UPSA/Bnstol-Myers Squibb Company, Rueil-Malmaison, France

Aim of Investigation To explore the dynamic relationship between pain intensity decrease (PID) and swelling reduction (SWD) over time dunng recovery from acute ankle sprain after topical treatment with the NSAID niflumic acid

Methods Data collected in a randomized, double-blind, placebo-controlled study were used for analysis and modeling of the relationship between PID at walk and SWD dunng 15 days post-trauma Individual values were normalized by linear transformation between 0 (no response) to 1 (disappearance of pain or swelling) Equations of clinically relevant models were fitted to the values of each group using iteratively non linear Marquardt method

Results The following (x, y) model provided the best and robust fit of the data of both groups (r = 0 98)

where K0, K1, K2 and K3 are constants

The first term was found to be dependent on the topical treatment factor and on the time KO was strongly dependent on the maximal swelling increase (range 0-8%) which occurred dunng the first four days in placebo patients, treatment with niflumic acid reduced Ko to zero The linear component was independent from treatment effect and may represent the basic healing process Multidimensional model [PID, SWD, time] will be presented and its relevance to the treatment effect of topical niflumic acid will be discussed.

Conclusion Pain decrease and swelling relationship dunng recovery from acute ankle sprain appeared different in placebo and niflumic acid-treated patients In clinical tnals, assessment of pain intensity is not necessanly a reliable surrogate of direct swelling measurement

ANTICEPHALGIC PHOTOPROTECTIVE PREMEDICATED MASK (APPM)

Morten L Hyson, Univ of Nevada, School of Medicine, 2020 Goldnng Ave , Ste 402, Las Vegas, Nevada 89106

Aim of Investigation A placebo-controlled, double-blind study was performed to determine the efficacy of an APPM in the treatment of migraines and/or tension-type headaches

Methods A placebo-controlled, double-blind study was performed over a penod of approximately two months There were 54 patients, 40 female and 14 male All had been referred to a neurologist for either migraines and/or tension-type headaches All had unremarkable CT or MR1 scans of the brain The patients were given masks and numbered bottles of topical medication containing topical salicm or placebo They were instructed to apply the medication to their frontalis region in the event they should suffer a headache, put on the photoprotective mask, and lie down Furthermore, they were instructed to take oral medications, if required, for relief of the headache They subsequently filled out forms rating the degree of relief which they attributed to the topical medications and the masks using a 0-10 scale They were also simply asked if this form of treatment helped or not

Results' Seven out of 20 of the patients who received the placebo stated that the medication and mask helped The placebo group gave it an average rating of 4 31 on a 0-10 scale Twenty-eight out of 34 of the patients receiving the salicm stated it was effective The salicm group rated it 7 42 on a 0-10 scale (p<0 001) Furthermore, the majonty of the patients receiving the salicm stated the duration of their headaches was significantly reduced as was their need for analgesic and/or narcotic medications for relief of the headache

Conclusions This study demonstrates a significant difference between the placebo and the salicm in association with the photoprotective mask in treating migraines and/or tension-type headaches with associated frontalis pain Not only did the patients receiving the salicm report significant relief from their headaches, they also noted the penod of time dunng which they suffered from the headaches was reduced as was their need for oral analgesic and/or narcotic medications

DEPTH OF CUTANEOUS ANALGESIA AFTER APPLICATION OF EMLA® CREAM

H.Ouidmg*.K Ericsson*,M Nilsson* and C F Wahlgren²* (Spon B Jonzon), Astra Pain Control AB, SE-151 85 Sodertalje, Sweden and Dept of Dermatology, Karolmska Hospital, SE-171 76 Stockholm, Sweden

Aim of Investigation To investigate depth of cutaneous analgesia using EMLA cream

Methods In a single-blind cross-over study EMLA cream was applied under occlusion on the thigh of 16 subjects Eleven had application times of 60 and 120 mm (ranges 55-65 and 119-131 mm) Five subjects had application times of 3-4 hours After EMLA removal, skin biopsy punch insertions (0 4 mm) were performed at increasing depths in steps of 1 mm down to 6 mm. After each insertion step the subject rated the pain intensity as acceptable or not acceptable; if not acceptable the insertions were stopped.

Results: The first table below gives the frequency of subjects (% out of 11) with acceptable pain at each insertion depth after 60 and 120 min. The mean depths with acceptable pain were 2.9 and 4.5 mm (pO.01, Wilcoxon) after 60 and 120 mm.

Treatment	1mm	2mm	3mm	4mm	5mm	6mm
EMLA 60 min EMLA 120 min	100% 100%	91% 100%	64% 91%	18% 73%	9% 45%	9% 36%

 The effect at the 3-4 h application is given below.

Treatment	4mm	5mm	6mm
EMLA 3-4 hours (n=5)	100%	100%	100%

Conclusions: The depth of cutaneous analgesia increases with application time of EMLA. Biopsy punch insertions are acceptable to depths of 1-2 mm after 60 mm, 2-3 mm after 120 mm and 6 mm after 3-4 hours. Punch insertions seem relevant for assessing depth of analgesia.

CHEMICAL AND PHYSICAL STABILITY OF MIXTURES OF ROPIVACAINE HYDROCHLORIDE AND DIFFERENT ANALGESIC DRUGS IN POLYPROPYLENE EPIDURAL INFUSION BAGS FOR THE MANAGEMENT OF POSTOPERATIVE PAIN

Kann Osier*. Magnus Carlsson*, Jane McKenzie*, Cheryl Larrivee-Elkins* (SPON: L. Alan), Astra Pharmaceutical Products Inc., 50 Otis St, Westborough, MA 01581-4500, U.S.A

Aim of Investigation: To investigate and establish the chemical and physical compatibility ofropivacame HCI solution for epidural infusion, 2 mg/ml and 1 mg/ml when admixed with either fentanyl, sufentanil, morphine sulfate or clonidine solution for injection at various clinical relevant concentrations in Polybag® for a time penod of up to 30 days.

Methods: The preparation of each admixture was completed asep-tically and stored at 30°C/40% RH for up to 30 days. Chemical and physical tests using stereomicroscope and high pressure liquid chromatography were performed initially and after 1, 14 and 30 days.

Results: Appearance, pH, ropivacame HCI content and fentanyl, sufentanil, morphine sulfate or clonidine content were all within the acceptance criteria through 30 days of storage. There was virtually no loss of potency of any drug.

Conclusions: Based upon the data collected, the combinations of ropivacaine HCI and either fentanyl, sufentanil, morphine sulfate or clonidine are chemically and physically compatible and stable for a time period of up to 30 days after preparation when stored in Polybag®. This opens up possibilities for the management of postoperative pain.

9th WORLD CONGRESS ON PAIN, 1999, Vienna, Austria, p. 62 - 70