Article

Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers

Clinical Pharmacology and Discovery Medicine, GlaxoSmithKline, Addenbrooke's Centre for Clinical Investigation, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2GG, UK.
BJA British Journal of Anaesthesia (Impact Factor: 4.35). 03/2007; 98(2):246-54. DOI: 10.1093/bja/ael344
Source: PubMed

ABSTRACT Central sensitization is an important mechanism of neuropathic pain; its human models could be useful for early detection of efficacy of novel treatments. The electrical hyperalgesia model invokes central sensitization by repetitive stimulation of the skin. To assess its predictive value, we have investigated pregabalin, a standard neuropathic pain treatment, and aprepitant, an NK(1) antagonist, as an example of a drug class active in animal models but not in neuropathic pain patients. Furthermore, we explored if combinations of either of these drugs with the COX-2 inhibitor parecoxib could improve its efficacy.
This was a double-blind, two-period, placebo-controlled study using incomplete block design. Thirty-two healthy volunteers received either oral pregabalin (titrated to 300 mg) or aprepitant (titrated to 320 mg), or matching placebo over 6 days before testing. Sensitization was assessed over 3 h; at 2 h, subjects received either parecoxib (40 mg) or saline i.v.
Pregabalin significantly reduced the areas of punctate mechanical hyperalgesia and dynamic touch allodynia vs placebo (both P < 0.0001); no significant reduction in the area of hyperalgesia or allodynia vs placebo was observed with aprepitant. In the pregabalin + parecoxib treated group, the area of allodynia was significantly reduced (P < 0.0001) and the area of hyperalgesia insignificantly attenuated (P = 0.09) vs placebo + parecoxib; no efficacy improvement was observed with aprepitant + parecoxib.
The model can serve to predict analgesic efficacy in early human development and investigate the mechanism of action. The model could also be used to explore efficacy of analgesic combinations to provide a rationale for patient studies.

0 Followers
 · 
87 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective The aim of this study was to evaluate the efficacy of prophylactic pregabalin on postdural puncture headache incidence and severity after spinal anesthesia. Method 86 ASA I-II male and female patients age 20–50 years old, undergoing elective general surgeries below the umbilicus under spinal anesthesia with 3 ml heavy bupivacaine 0.5% (15 mg), patients were randomly allocated into one of two groups (Group C, n = 43) (control group) received a placebo capsule 2 h preoperatively (Group P, n = 43) received 150 mg pregabalin capsule 2 h preoperatively, number of attempts for spinal block, sensory level, motor block grade, postoperative time to first analgesic requirement, the incidence, onset and intensity of PDPH and adverse events were recorded for 72 h. Results The peak sensory level in C group and P group showed no statistical significant difference, the time to peak sensory block was significantly earlier in P group than group C, the time to reach the modified Bromage motor block grade 3 was significantly earlier in P group than C group, time to two segment regression of sensory level to S1 and motor block regression to modified Bromage grade 0 were statistically insignificant between the studied groups. Group P had a significantly longer time to first analgesic requirements than group C, and there was no significant difference in VAS (visual analogue scale) of pain between the studied groups. There was significant increase in sedation score in P group compared to C group at 2 h and 6 h postoperatively, and there was statistically significant reduction in the incidence rate and severity of PDPH in P group compared to group C. There were no recorded cases of dizziness, visual disturbances, or PONV. Conclusions preoperative oral pregabalin 150 mg reduced the incidence and severity of PDPH, beside the earlier onset of peak sensory and motor block with increase duration of analgesia in patients undergoing elective surgeries under spinal anesthesia.
    10/2013; 29(4):357–361. DOI:10.1016/j.egja.2013.04.001
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
    Pain 10/2010; 152(3 Suppl):S2-15. DOI:10.1016/j.pain.2010.09.030 · 5.84 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This was a multicenter, double-blind (DB), placebo-controlled, randomized discontinuation trial to evaluate the efficacy of pregabalin monotherapy for durability of effect on fibromyalgia (FM) pain. The trial included a 6-week open-label (OL) pregabalin-treatment period followed by 26-week DB treatment with placebo or pregabalin. Adults with FM and 40-mm score on 100-mm pain visual analog scale (VAS) were eligible. During OL weeks 1-3, patients received escalating dosages of pregabalin to determine their optimal dosages. During OL weeks 4-6, patients received their optimal fixed dosages (300, 450, 600mg/d). To be randomized, patients must have had 50% decrease in pain VAS and a self-rating of "much" or "very much" improved on Patient Global Impression of Change (PGIC) at the end of OL. Double-blind treatment was with placebo or the patient's optimal fixed dosage of pregabalin. Primary outcome was time to loss of therapeutic response (LTR), defined as <30% reduction in pain (from OL baseline) or worsening of FM. A total of 1051 patients entered OL; 287 were randomized to placebo, 279 to pregabalin. Time to LTR was longer for pregabalin versus placebo (P<.0001). Kaplan-Meier estimates of time-to-event showed half the placebo group had LTR by Day 19; half the pregabalin group still had not lost response by trial end. At the end of DB, 174 (61%) placebo patients met LTR criteria versus 90 (32%) pregabalin patients. Pregabalin was well tolerated, though 178 (17%) discontinued during OL for treatment-related adverse events (AE), and more pregabalin than placebo patients discontinued for AEs during DB. In those who respond, pregabalin demonstrated durability of effect for relieving FM pain.
    Pain 06/2008; 136(3):419-31. DOI:10.1016/j.pain.2008.02.027 · 5.84 Impact Factor

Similar Publications