efficacy & safety study of nonracemic methadone for the relief of chronic peripheral neuropathic pain

Conditions: Diabetic Peripheral Neuropathic Pain

Summary: there is a growing evidence that the d-isomer of methadone is effective in treating neuropathic pain while the l-isomer of methadone is the only effective isomer of methadone for treating somatic pain. this study will examine a combination of different amounts of the d- and l-isomers of methadone specifically tailored to the chronic peripheral neuropathic pain. non-racemic mixture of methadone isomers will be tested in this pilot efficacy and safety study. this study will evaluate effect of the three doses of the non-racemic mixture of methadone hydrochloride patients with chronic peripheral neuropathic pain compared with a placebo. the study will also examine the minimally effective and maximally tolerated doses of the non-racemic mixture of methadone. finally, the safety and tolerability of the non-racemic methadone therapy will be evaluated.

objectives: * to evaluate effect of the three doses of the non-racemic methadone hcl on the metrics of pain intensity in comparison to placebo. * to determine minimally effective and maximally tolerated doses of non-racemic methadone hcl for the treatment of diabetic peripheral neuropathic pain. * to evaluate safety and tolerability of non-racemic methadone hcl therapy. study design: this is a pilot efficacy and safety study comprised of two parts. part i is a double-blind, placebo-controlled, crossover study of three daily doses (15 mg, 30 mg and 40 mg) of non-racemic methadone compared with placebo. two lower doses (15 mg and 30 mg) will be administered for 1 week. the final dose (40 mg) will be administered for 2 weeks. after receiving three consecutive doses of the assigned drug the subjects will be switched to another regimen. two 28-day treatment periods will be separated by a 14-day washout (drug-free) interval. subjects will be randomly assigned to one of the two treatment sequences: sequence 1: non-racemic methadone hcl (period 1) followed by placebo (period 2); sequence 2: placebo (period 1) followed by non-racemic methadone hcl (period 2). subjects completing part i will be enrolled into the open-label, single-arm extension. subjects discontinuing the study while on placebo may also be eligible for the enrollment. during the 6-week extension phase (part ii of the study) subjects will be treated with non-racemic methadone hcl with continuous dose titration driven by the clinical response (degree of pain relief) and reported adverse events. the parts i and ii will be separated by a 14-day washout (study drug-free) interval. number of patients: up to fifty (50) subjects diagnosed with neuropathic pain associated with diabetic peripheral neuropathy will be enrolled in the study; approximately 30 subjects are expected to complete study part i. enrollment will be terminated when this completion target is achieved. study duration: the duration of study part i is approximately 12 weeks, the duration of study part ii is approximately 6 weeks. a total study duration (including screening and final evaluations) is expected to be approximately 20 weeks.

Eligibility criteria:
inclusion criteria: * male or female 18 years of age or older; * female with a negative serum βhcg pregnancy test * female of non-childbearing potential (postmenopausal or surgically sterile) or female of child-bearing potential agreed to use the protocol-approved contraceptive method * documented diagnosis of neuropathic pain associated with diabetic peripheral neuropathy for at least 6 months * average daily pain severity score \>=4 for the seven days prior to randomization (based on an 11-point numerical rating scale where 0= no pain and 10=worst possible pain) * score \>= 40 mm on the vas of the short form mcgill pain questionnaire (sf-mpq) at screening and randomization visits * stable doses (for at least three weeks) of non-opioid analgesics including nsaids, corticosteroids, gabapentin, pregabalin or antidepressants prescribed for the purposes of pain control or pain treatment naïve * willing to refrain from any pain-relieving drugs other than the protocol-approved rescue medications (acetaminophen, \<= 3 g daily or aspirin \<= 325 mg daily) during the screening phase and the course of the study * willing to limit alcohol consumption during the study according to protocol requirements * able to understand and complete study diary and questionnaires * willing to give informed consent prior to entry into the study exclusion criteria: * a documented neuropathy of any cause other than diabetic peripheral neuropathy * a severe intermittent pain for reasons other than radiculopathy (e.g., migraine attacks) * history of head injury and/or increased intracranial pressure * any neurologic disorder unrelated to diabetic peripheral neuropathy * non-adequate renal and/or hepatic function as follows: serum creatinine \> 1.5 x uln (upper limit of normal range) liver enzymes (alt and ast) \> 2 x uln * any other know laboratory abnormality that, in the investigator's opinion, would contraindicate study participation * chronic hepatitis b, hepatitis c, or hiv infection * abnormal cognition defined as obvious clinical findings of state of arousal, confusion and memory or concentration deficit. * recent history (within the previous 12 months) of respiratory depression, acute bronchial asthma or hypercarbia, or any other severe pulmonary or respiratory disease * recent history (within the previous 12 months) of sleep apnea * any hemostatic disorders or a current treatment with anticoagulants; * unstable cardiovascular disease or symptomatic peripheral vascular disease * hypotension: sitting or standing systolic blood pressure \ 20 mmhg and/or a difference between sitting and standing diastolic blood pressure \>10 mmhg) * any clinically important ecg abnormality (including qt interval exceeding 450 ms) * recent history (within the last 12 months) of risk factors for development of prolonged qt interval, including cardiac hypertrophy, concomitant diuretic use, hypocalcemia, hypomagnesemia

Keywords: peripheral neuropathic pain