Hoggart, B.

Ratcliffe, S.

Serpell, M.G.

Simpson, K.

English

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Stable dose cannabinoid medicine (Sativex®, THC+CBD) can provide sustained efficacy in the treatment of refractory painful diabetic neuropathy or other peripheral neuropathic pain associated with allodynia [poster]

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       Ratcliffe , S. and Serpell, M.G. and Hoggart, B. and Simpson, K. (2008) Stable dose cannabinoid medicine (Sativex®, THC+CBD) can provide sustained efficacy in the treatment of refractory painful diabetic neuropathy or other peripheral neuropathic pain associated with allodynia. In: International Association for Pain and Chemical Dependency Conference, 29 Oct - 1 Nov 2008, Philadelphia, USA.  http://eprints.gla.ac.uk/5268/  Deposited on: 06 April 2010   Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk » BACKGROUNDStable dose cannabinoid medicine (Sativex®, THC+CBD) can provide sustained efficacy in the treatment of refractory painful diabetic neuropathy or other peripheral neuropathic pain associated with allodynia.Ratcliffe S1, Serpell MG2, Hoggart B3, Simpson K41MAC UK Neuroscience Ltd., Blackpool, UK; 2Gartnavel General Hospital, Glasgow, UK; 3Solihull Hospital, Solihull, UK; 4Seacroft Hospital, Leeds, UK.» CONCLUSIONNeuropathic Pain (NP) poses a major challenge:  • Most common long-term complication of diabetes mellitus• Leads to great morbidity and mortality• Results in a huge economic burden for diabetes care• Can be a disabling and painful symptom• Existing treatments afford only partial relief and have unpleasant side-effects• Sativex remained well tolerated and beneficial for the majority of subjects with peripheral neuropathic pain secondary to diabetes or associated with allodynia over nine months.• Maintenance in pain relief was achieved without an increase in dose of Sativex.• The study raised no new safety concerns for Sativex. 2. Baseline Subject Characteristics3. Mean NRS Pain Scores 7. Safety• 295 subjects reported at least 1 treatment-emergent AE; 224 subjects (59%) were related• 88 subjects (23%) reported at least 1 AE leading to permanent cessation of study medication.• Severe AEs affected 87 subjects (23%).• 40 subjects (11%) reported at least one SAE; 4 subjects (1%) were related:• 2 subjects experienced amnesia, 1 resolved following discontinuation of Sativex and 1 was still ongoing at last visit; 1 subject experienced paranoia which resolved following discontinuation of Sativex; 1 suicide attempt occurred 26 days after last dose.• 2 fatal non-related AEs occurred.4. Responders at the 30% and 50% Level of Improvement 6. Secondary Endpoints1. Disposition of SubjectsThere was an improvement over the initial weeks of treatment and subsequent maintenance of benefit.Common adverse events (occurring in 5% or more subjects)No. of Subjects (%) (n=380)Gender Male 200 (53%)Female 180 (47%)Ethnic Origin White/Caucasian 374 (98%)Other 6 (2%)Previous Cannabis Use (at any time, prior to parent RCTs) 38 (10%)Mean (SD)Age (years) 57.8 (12.03)BMI (kg/m2) 29.9 (6.76)Duration of Any Underlying Condition Causing PNP (years) 9.63 (8.45)Duration of PNP (years) 5.35 (5.30)After 9 months of open label Sativex treatment, 141 (61%) completing subjects reported pain scores that were improved by ≥30% from the parent RCT baseline 12 months earlierSystem Organ ClassPreferred TermAll-Causality Number (Percentage) of Subjects                                 Treatment-RelatedNumber (Percentage) of SubjectsTotal subjects with at least one AE 295 (78%) 224 (59%)Nervous System DisordersDizzinessDysgeusiaSomnolenceHeadache168 (44%)79 (21%)29 (8%)28 (7%)23 (6%)140 (37%)74 (19%)28 (&%)27 (7%)11 (3%)Gastrointestinal DisordersNauseaDry MouthVomiting135 (36%)42 (11%)30 (8%)25 (7%)97 (26%)35 (9%)29 (8%)11 (3%)General Disorders and Administration Site ConditionsFatigueFeeling Drunk92 (24%)31 (8%)21 (6%)69 (18%)27 (7%)21 (6%)Psychiatric DisordersDisorientation79 (21%)19 (5%)55 (14%)18 (5%)0102030405060701 2 3 4 5 6 7 8 9Study Period (Month)Percentage of Subjects30% Response50% ResponseN=336        317                 298           276              262               261               245          237           230N=336        317                 298             276            262               261              245             237         230-4-2024680 End ofParentTitration 1 2 3 4 5 6 7 8 9Study Period (Month)Mean Pain NRS-11 (+/- SE)Change from BaselineAbsolute ValuesN=380  380 365         336        317          298        276  262          261        245       237           230» METHODSStudy Design:• 38-week open label, follow-on studyStudy Objectives:• To evaluate maintenance of effect and development of tolerance through exposure to, and safety of open label Sativex therapy in subjects with peripheral neuropathic pain (PNP)Study Population:• 380 subjects who had participated in one of two 3-month (GWCL0305 and GWCL0405), double blind, randomised controlled clinical trials (parent RCT) designed to investigate the role of Sativex in the treatment of PNP secondary to diabetes or associated with allodyniaAssessments:• Primary endpoint was pain severity scores recorded using a 0-10 Numerical Rating Scale (NRS-11)• Secondary endpoints included theNeuropathic Pain Scale (NPS), sleep disturbance NRS-11, Subject Global Impression of Change (SGIC), intoxication NRS-11 and a quality of life EQ-5D health questionnaire• Safety was assessed by monitoring adverse events (AEs) and serial clinical chemistry and vital signsStudy drug: Sativex® (THC:CBD) endocannabinoid system modulator• Approved in Canada for relief of central neuropathic pain in Multiple Sclerosis and cancer pain• Produced from selected strains of cloned Cannabis sativa plants formulated into a spray for oromucosal administration• Highly standardised formulation: each 100µl spray of Sativex® contains 2.7 mg delta-9-tetrahydrocannabinol (THC), 2.5 mg cannabidiol (CBD), minor cannabinoids (5-6%) and small amounts of other plant extracts such as terpenes• Subjects self-titrated to their optimal dose on the basis of their individual efficacy and tolerability response, up to a maximum of 24 sprays/dayRationale for Treatment:• Previous clinical trials have shown that Sativex has analgesic properties that are effective in relieving neuropathic pain• These studies also suggested that Sativex is well tolerated and may also improve sleep and quality of life• Pain resulting from diabetic neuropathy is often not satisfactorily alleviated by existing therapiesNPS and Sleep Quality NRS-11• Improvement maintained with time and continued to improve up to week 26 (change from parent RCT baseline was -21.51 for the NPS and -2.39 for the sleep NRS-11)SGIC• 70% of subjects had an improvement in nerve pain• 8% of subjects had a worsening in nerve painHealth Outcomes – EQ-5D Questionnaire Score• Descriptive System Questionnaires (Mobility, Activity, Self care, Pain and Anxiety):-More subjects improved than worsened in their classification form parent RCT baseline• Weighted Health State Index and Health Status VAS:- Small improvement in both index and VAS scores, maintained at final visitIntoxication Scores• Mean intoxication scores throughout course of study were less than 2 points out of 10» RESULTS5. Dosing Data0123456789101 2 3 4 5 6 7 8 9Study P erio d (M o nth)N= 340             320              301             281  266              262              245               237              231

Stable dose cannabinoid medicine (Sativex®, THC+CBD) can provide sustained efficacy in the treatment of refractory painful diabetic neuropathy or other peripheral neuropathic pain associated with allodynia [poster]

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