Bottlenecks in the development of topical analgesics: molecule, formulation, dose-finding, and phase III design

Abstract

Topical analgesics can be defined as topical formulations containing analgesics or co-analgesics. Since 2000, interest in such formulations has been on the rise. There are, however, four critical issues in the research and development phases of topical analgesics: 1) The selection of the active pharmaceutical ingredient. Analgesics and co-analgesics differ greatly in their mechanism of action, and it is required to find the most optimal fit between such mechanisms of action and the pathogenesis of the targeted (neuropathic) pain. 2) Issues concerning the optimized formulation. For relevant clinical efficacy, specific characteristics for the selected vehicle (eg, cream base or gel base) are required, depending on the physicochemical characteristics of the active pharmaceutical ingredient(s) to be delivered. 3) Well-designed phase II dose-finding studies are required, and, unfortunately, such trials are missing. In fact, we will demonstrate that underdosing is one of the major hurdles to detect meaningful and statistically relevant clinical effects of topical analgesics. 4) Selection of clinical end points and innovatively designed phase III trials. End point selection can make or break a trial. For instance, to include numbness together with tingling as a composite end point for neuropathic pain seems stretching the therapeutic impact of an analgesic too far. Given the fast onset of action of topical analgesics (usually within 30 minutes), enrichment designs might enhance the chances for success, as the placebo response might decrease. Topical analgesics may become promising inroads for the treatment of neuropathic pain, once sufficient attention is given to these four key aspects.

Itch: From mechanism to (novel) therapeutic approaches

“…118 Centrally, amitriptyline behaves largely as a serotonin-norepinephrine reuptake inhibitor; however, the topical effects of amitriptyline are believed to include antagonism of voltage-gated ion channels and a number of other receptors (eg, adrenergic, cholinergic, histaminergic, muscarinic, and N-methyl-D-aspartate receptors). 119 Applying cool temperatures to the skin can reduce itch intensity and duration. 120 This mechanism involves activation of TRPM8 on afferent neurons, which can then activate inhibitory pathways to reduce itch (Fig 2).…”

A review of the clinical applications of ketamine in pediatric oncology

“…94 TA B L E 3 Prospective trials of ketamine for procedural pain or sedation in children with cancer (sample size ≥ 10) and decreased risk of abuse or dependence. 95 Considering these benefits and the fact that the patients with cancer are already on a concoction of systemic agents, discovering effective topical agents could prove very useful in this group in providing desired therapeutic effects while minimizing adverse effects and harmful drug interactions. 96 Hence, further studies investigating the topical delivery of ketamine for analgesic and anti-inflammatory effects need to be encouraged.…”

Topical Compounded Analgesic Treatment in Neuropathic Pain: 8 years of Experience

“…Without wanting to go too much into detail here, various physicochemical characteristics, such as molecular weight, melting point, the partition coefficient, the capacity factor, and aqueous saturation solubility, all play important roles [12]. For instance, in order to penetrate the outer skin layer, a compound needs to have lipophilic characteristics and a relatively low molecular weight; it needs to be a small molecule [8]. Furthermore, the compounds need to be soluble in the selected vehicle, which in turn needs to be smearable, non-sticky and not unpleasant for patients when they rub it in.…”

“…Studies comparing the combination of amitriptyline 2% and ketamine 1% to placebo were found to be negative [6,7]. We felt that dose-ranging in topical studies has been conducted in a suboptimal way, and one should aim for much higher dose-ranges [8].…”