P38 Mitogen-activated Protein (Map) Kinase Inhibitor (SB-681323)Study In Patients With Neuropathic Pain

• Sensory thresholds (warm perception, heat pain, cold perception, cold pain) in the affected and control area Use of rescue medication Safety [ Time Frame: over Week 1 and Week 2 of the treatment ]
• ·Patient's global impression of change
• ·Physician's global impression of change
• ·Use of rescue medication (Week 1 and Week 2)
• ·Sensory thresholds (warm perception, heat pain, cold perception, cold pain) in the affected and control area
• ·Intensity of pain (using the 11 point NRS) evoked by topical capsaicin challenge (optional)
• ·Change in heat pain threshold (heat hyperalgesia) in response to capsaicin skin challenge (optional)
• ·Area and intensity of flare evoked by capsaicin (optional)
• ·Area and intensity of dynamic touch allodynia (when present)
• ·Evoked potentials in response to pulses of noxious heat (CHEPs) in the affected and control (mirror image site) area (optional)
• ·Capsaicin and heat receptor TRPV1 immunoreactivity and mechanism-related markers (NGF, CGRP) in skin biopsies in some patients
• (optional: some patients may proceed to surgery after their participation in the trial is complete, and may consent to incisional skin biopsy being taken for this study)
• ·Adverse events
• ·Vital signs (blood pressure and heart rate)
• ·12-Lead ECG
• ·Continuous ECG monitoring
• ·Safety laboratory tests (haematology, clinical biochemistry, urinalysis, pregnancy test)

This will be a double-blind, placebo controlled cross-over study. After enrolment and initial assessments, subjects will receive oral SB681323 or matching placebo for 14 days. SB681323 will be administered twice daily at a total daily dose of 7.5mg. Sufficient numbers of patients will be recruited to obtain 40 evaluable patients

• Pain, Neuropathic
• Neuropathic Pain
• Nerve Trauma

Inclusion criteria:

• A subject will be eligible for inclusion in this study only if all of the following criteria apply:

Male or female subjects 18-80 years of age

• To be eligible, females patients must have a negative pregnancy test (i.e. serum beta hCG test) and be of:

  1. non-childbearing potential (i.e. physiologically incapable of becoming pregnant). This includes any female who is post-menopausal. For the purposes of this study, post menopausal is defined as being amenorrhoeic for greater than 2 years with an appropriate clinical profile, e.g. age appropriate, history of vasomotor symptoms. Postmenopausal status will be confirmed by serum FSH and oestradiol concentrations at screening. Surgical sterility will be defined as females who have had a hysterectomy and/or bilateral oophorectomy or tubal ligation.

OR b.childbearing potential and agree to commit to one of the protocol-approved methods of contraception, when used consistently and in accordance with both the product label and the instructions of a physician, as indicated below: i.oral contraceptive (combined or progestin only), and the same oral contraceptive regimen has been used for at least two months prior to study drug administration, and the same method continues throughout the study and through the follow-up phase of the study.

ii.progesterone implanted rods (Norplant ) inserted for at least two months prior to the study drug administration (but not beyond the third successive year following insertion) , and is continued throughout the study and through the follow-up phase of the study.

iii.an IUD, inserted by a qualified clinician, with published data showing that the highest expected failure rate is less than 1% per year (not all IUDs meet this criterion) Acceptable IUDs: TCu-380A (Paragard), TCU-380 Slimline (Gyne T Slimline), TCu-220C, MULTILOAD-250 (MLCu-250) and 375, NOVA T and CUNOVAT (Novagard), Levonorgesterol (LNG-20) Intra-uterine System (Mirena/Levonova), and FlexiGard 330/CuFix PP330 (Gynefix). The device must be inserted at least 2 weeks prior to the Screen visit, and remain throughout the study and through the follow-up phase of the study.

iv.injectable medroxyprogesterone acetate (e.g., Depo-Provera) and is on a stable dose for 2 months prior to Screen, throughout the study and through the follow-up phase of the study.

v.complete abstinence from intercourse from at least two weeks prior to Screen, throughout the treatment phase, and the follow-up phase.

vi.double barrier method if comprised of a spermicide with either a condom or diaphragm from at least two weeks prior to Screen, throughout the treatment phase, and the follow-up phase.

• A diagnosis of peripheral neuropathic pain:

  • focal neuropathic pain related to nerve injury caused by trauma or surgery not associated with ongoing infection (examples include post-thoracotomy syndrome, post-mastectomy syndrome, post-inguinal herniorrhaphy syndrome, post-radical neck dissection syndrome, traumatic mononeuropathies- bullet wounds, lacerations, road traffic accidents)
  • pain associated with lumbo-sacral radiculopathy; patients with radiculopathy will only be included if they have pain radiating below the knee and have loss of small fibre function as indicated by quantitative sensory testing (elevation of at least one sensory modality threshold in the symptomatic limb - warm sensation > 9.6 0C and cool sensation > 5.6 0C - in L4, L5 or S1 dermatomes) [Quraishi, 2004].
  • carpal tunnel syndrome (CTS); patients with CTS will only be included if there is evidence of loss of large and small fibre function (confirmed by an electrophysiological nerve conduction examination and by quantitative sensory testing - warm sensation > 5.2 0C and cool sensation > 4.5 0C - in median nerve territory (Anand et al., unpublished data).
  • location of pain consistent with the area innervated by the affected nerve(s), with or without other sensory symptoms in the affected area
  • at least three months duration
• Baseline pain intensity score averaging ≥ 4 during the three day prior to study start as reported on the 11 point pain intensity numerical rating scale. For CTS patients, peak daily pain will be ≥4 for at least 3 days prior to enrolment
• Subjects who have received nerve blocks or steroid injections for neuropathic pain may be included if their most recent nerve block was at least 4 weeks prior to randomisation.
• Body weight ≥ 50 kg (110 lbs) for men and ≥ 45 kg for women, Body Mass Index 18.5-35kg/m2.
• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) within normal limits at screening.
• The subject is able to understand and comply with protocol requirements, instructions and protocol-stated restrictions.
• Signed and dated written informed consent prior to admission to the study.

Exclusion criteria:

• A subject will not be eligible for inclusion in this study if any of the following criteria apply:

• Any clinically significant medical history or abnormality found on physical examination, laboratory assessment or ECG at screening which, in the opinion of the investigator, could interfere with the interpretation of efficacy or safety data or which otherwise would contraindicate participation in a clinical study, in particular:

  • subjects with non-neuropathic pain component involvement, mononeuropathy multiplex, or more than one cause or potential cause for pain symptoms (e.g. trigeminal neuralgia, painful diabetic neuropathy, central post-stroke pain, phantom limb pain, peripheral neuropathy due to alcoholism, malignancy, HIV, syphilis, drug abuse, vitamin deficiency, hypothyroidism, liver disease, toxic exposure, or chronic neck pain);
  • subjects with intractable pain of unknown origin or active infection in the area of nerve injury/compression;
  • subjects who have had extensive surgery in the treatment of their nerve injury;
  • history of Gilbert's syndrome or elevated bilirubin levels (total, direct or indirect) in a previous clinical study or at screening;
  • history of increased liver function tests (ALT, AST) above upper limit of normal in the past 6 months;
  • positive Hepatitis B surface antigen, positive Hepatitis C antibody or Hepatitis C nucleic acid result;
  • GI disorders that may interfere with safety assessments, e.g. diarrhoea.
• Recent start or change in dosing regimen (£1 month prior to screen) of any medication which, in the opinion of the Investigator, may interfere with pain assessments or introduce a risk of drug-drug interactions (e.g. glucocorticoids and some anticonvulsants, see Section 9.2, Prohibited Medications for details).
• Unable to refrain from excessive use medications (e.g. sedatives) that in the opinion of Investigator may interfere with efficacy or safety assessments (benzodiazepines prescribed as hypnotic sleep agents allowed). Subject is unable to discontinue topical analgesics prior to randomization and for the duration of the study. In the case of topical capsaicin this will be extended to 4 weeks.
• Subject is unable to refrain from nerve blocks during the study.
• Positive alcohol test or urine drug screen at screening.
• History of regular alcohol consumption exceeding an average weekly intake of > 21 units (or an average daily intake of greater than 3 units) for males, or an average weekly intake of > 14 units (or an average daily intake of greater than 2 units) for females.
• Consumption of grapefruit or grapefruit juice within seven days prior to the first dose of study medication.
• Donation of blood in excess of 500 mL within a 30-day period prior to dosing.
• Participation in a trial with any drug within 3 months before the start of the study or participation in a trial with a new chemical entity within 4 months before the start of the study.
• Pregnant or nursing female subjects.
• Known history of hypersensitivity or intolerance to paracetamol products.
• Inability or unwillingness to follow the instruction of the study protocol.
• Known hypersensitivity to capsaicin (if applicable)
• An unwillingness of male subjects to abstain from sexual intercourse with women; or unwillingness of the male subject to use a condom/spermicide in addition to having their female partner use another form of contraception (as described in inclusion criterion for women) if the woman could become pregnant from the time of the first dose of investigational product until completion of the follow-up procedures.