Time to Onset of Neuropathic Pain Reduction: A Retrospective Analysis of Data From Nine Controlled Trials of Pregabalin for Painful Diabetic Peripheral Neuropathy and Postherpetic Neuralgia

Abstract

These retrospective analyses of daily mean pain scores from nine placebo-controlled trials of pregabalin at 150, 300, or 600 mg/day (pregabalin, n = 1205; placebo, n = 772) examined time to significant reduction of pain during the first 2 weeks of treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. Time to onset of reduction in pain-defined as the first day for which patients treated with pregabalin had significant reductions (P < 0.05) in mean pain score compared with the placebo group for that day and the subsequent day-was calculated for all treatment groups demonstrating statistically significant reduction in pain at trial end point. The time to a 1-point or greater improvement in mean pain score was measured for each patient who was a responder at end point (30% or greater improvement in mean pain score). In seven of the nine trials (representing 11 of 14 pregabalin arms), significant reduction in pain was achieved at end point. The time to onset for reduction in pain was treatment Day 1 or 2 in nine of these successful treatment arms. Individual responder analysis confirmed that responders in the pregabalin groups reported a 1-point or greater pain reduction earlier than responders in placebo groups (P < 0.0001). However, this analysis is not a direct estimate of the likelihood that an individual patient would experience noticeable pain relief by the end of the second day. Overall, for patients who will respond to pregabalin, statistically significant and sustained reduction of pain associated with diabetic peripheral neuropathy and posttherapeutic neuralgia occurs early, usually by the end of 2 days of pregabalin treatment.

Analysis of the long-term actions of gabapentin and pregabalin in dorsal root ganglia and substantia gelatinosa

“…Since clinical benefit from gabapentinoids takes 3 or more days to develop in the clinic (Cheshire 2002;Sharma et al 2010), our studies were designed to replicate this situation in vitro. In confirmation of the results of Moore et al (2002), we found that gabapentinoids had little or no effect in spinal cord when applied acutely (Table 2).…”

“…Because neuropathic pain is characteristically resistant to the actions of conventional analgesics, treatment often involves the use of "antiallodynic" agents such as pregabalin (PGB) or gabapentin (GBP) (Moulin et al 2007). In the clinic, these drugs take at least 3 days to exert an effect (Cheshire 2002;Sharma et al 2010). Gabapentinoids are transported into neurons via the neutral amino acid transporter (Su et al 1995), where they interact with the ␣2␦-1 accessory subunits of voltage-gated calcium channels (Bauer et al 2009;Davies et al 2007;Field et al 2006;Gee et al 1996;Hendrich et al 2008;Patel et al 2013).…”

Etiology and Pharmacology of Neuropathic Pain

“…In the case of primary afferent neurons, a2d is implicated in the relatively slow trafficking of a subunits of HVA-Ca 2+ channels from their site of synthesis in the cell body, along primary afferent axons, to their terminals in the spinal dorsal horn (Bauer et al, 2009). It is tempting to speculate that attenuation of this slow trafficking process by gabapentinoids corresponds to reports of their slow onset of action in neuropathic pain patients (Cheshire, 2002;Stacey et al, 2008;Sharma et al, 2010), but, as discussed in Rate of Onset of Gabapentinoid Effect, we think this is unlikely to be the case.…”

“…Despite their rapid efficacy in animal models of neuropathic pain (Hunter et al, 1997;Field et al, 2006;Narita et al, 2012;Kumar et al, 2013;Alles and Smith, 2016;Alles et al, 2017), several reports indicate that GBP effects in clinical pain management take a day or more to develop (Cheshire, 2002;Stacey et al, 2008;Sharma et al, 2010;Rauck et al, 2013).…”

Examining the Time to Therapeutic Effect of Pregabalin in Spinal Cord Injury Patients With Neuropathic Pain

“…In an analysis of data from 9 placebo-controlled trials in patients with neuropathic pain due to diabetic peripheral neuropathy or postherpetic neuralgia, the time to significant pain relief usually occurred within 2 days of initiating treatment with pregabalin. 19 Similarly, the time to significant relief of pain-related sleep interference was estimated at 1 to 2 days in a retrospective analysis of 16 placebo-controlled trials of pregabalin in patients with painful diabetic peripheral neuropathy or post-herpetic neuralgia. 20 Timing of pregabalin's therapeutic effect was also examined in a retrospective analysis of 4 placebo-controlled trials in patients with fibromyalgia, whereby the time to significant improvement in pain and sleep quality was estimated at 1 to 2 days.…”