Tolerability and Analgesic Efficacy of Loxapine in Patients With Refractory, Chemotherapy-induced Neuropathic Pain

Loxapine is an antipsychotic drug approved for the treatment of schizophrenia in several countries including the United States. In animal studies in mice, loxapine reduced neuropathic pain. Hence, in a proof-of-principle and dose-escalating study the tolerability and analgesic efficacy of loxapine will be evaluated in patients with neuropathic pain.

In this dose-escalating study, 12 patients with refractory, chemotherapy-induced neuropathic pain (including mixed pain) will receive loxapine during four 14-days treatment episodes. The dosage for episode 1 (Days 1-14) will be 10 mg b.i.d., dosages for episodes 2, 3, and 4 will be defined by taking into account tolerability and analgesic efficacy of the former episode. In case of an acceptable tolerability and if a clinically relevant analgesic efficacy is not reached, loxapine dosage will be increased (2nd Episode 10 mg t.i.d, 3rd Episode 20 mg b.i.d., 4th episode 20 mg t.i.d.). In case of an acceptable tolerability and if a clinically relevant analgesic efficacy is reached, loxapine dosage will not be changed. If clinically relevant (serious) adverse events ((S)AEs) occur, loxapine dosage will be reduced or the treatment will be interrupted or stopped irrespective of the analgesic efficacy. A clinically relevant pain reduction / analgesic efficacy is defined by an at least 30% decrease or an absolute decrease of two scale units compared to baseline using 11-point numeric pain rating scale. Patients will receive loxapine as add-on treatment to their usual (analgesic) care.

Eligibility Criteria:
Inclusion Criteria:

* Primarily chemotherapy-induced neuropathic pain (including mixed pain) for at least 3 months refractory to at least one analgesic compound
* Neuropathic pain \>= 4 (11-point numeric pain scale) at screening visit (including mixed pain)
* Age \>= 18 years
* Body weight between 50 and 150 kg
* Given written informed consent

Exclusion Criteria:

* Participation in other interventional clinical studies (currently or within the last 3 months)
* Parkinson's disease, movement disorders (extrapyramidal signs and symptoms) associated with antipsychotics, neuroleptic malignant syndrome, other syndromes associated with antipsychotics
* Severe hypotension with a syncope in history, glaucoma, urinary retention, epilepsy or other seizure disorders in history, severe dementia, dementia-related psychosis in history, malignancies with a life expectancy of less than 6 months, breast cancer in history, other life-threatening conditions
* Corrected QT interval (QTc) \> 460 ms (females) or \> 450 ms (males)
* Known alcohol and/or drug abuse
* Concomitant intake of antipsychotics, dopamine agonists (Levodopa, bromocriptine, lisuride, pergolide, ropinirole, cabergoline, pramipexole, apomorphine), alpha-receptor blocking compounds
* Compounds with a strong evidence for a clinically relevant QT interval prolongation or torsade de pointes risk increase
* Strong inhibitors of CYP1A2, CYP2D6, or CYP3A4
* Known CYP2D6 Poor metabolizer status
* Pregnancy or lactation period
* Missing or insufficient contraception in pre- or perimenopausal women
* Close Affiliation with the investigational site