Effects of target-controlled infusion of high-dose naloxone on pain and hyperalgesia in a human thermal injury model: a study protocol: A randomized, double-blind, placebo-controlled, crossover trial with an enriched design

Abstract

Mu-opioid-receptor antagonists have been extensively studied in experimental research as pharmacological tools uncovering mechanisms of pain modulation by the endogenous opioid system. In rodents, administration of high doses of mu-opioid-receptor antagonists after the resolution of an inflammatory injury has demonstrated reinstatement of nociceptive hypersensitivity indicating unmasking of latent sensitization. In a recent human study, pain hypersensitivity assessed as secondary hyperalgesia area (SHA), was reinstated 7 days after a mild thermal injury, in 4 out of 12 subjects after a naloxone infusion.The aims of the present study are first, to replicate our previous findings in a larger-sized study; second, to examine if high sensitizers (subjects presenting with large SHA after a thermal injury) develop a higher degree of hypersensitivity after naloxone challenge than low sensitizers (subjects presenting with restricted SHA after a thermal injury); and third to examine a dose-response relationship between 3 stable naloxone concentrations controlled by target-controlled infusion, and the unmasking of latent sensitization.Healthy participants (n = 80) underwent a screening day (day 0) with induction of a thermal skin injury (47°C, 420 seconds, 12.5 cm). Assessment of SHA was performed 1 and 2 hours after the injury. Using an enriched design, only participants belonging to the upper quartile of SHA (Q4, high sensitizers; n = 20) and the lower quartile of SHA (Q1, low sensitizers; n = 20) continued the study, comprising 4 consecutive days-days 1 to 4. Thermal skin injuries were repeated on day 1 and day 3, whereas day 2 and day 4 (7 days after day 1 and day 3, respectively) were target-controlled infusion days in which the subjects were randomly allocated to receive either naloxone (3.25 mg/kg, 4 mg/mL) or placebo (normal saline) intravenous. The primary outcome was SHA assessed by weighted-pin instrument (128 mN) 0, 1, 2, and 165 to 169 hours after the thermal injury (day 1-4). The secondary outcomes were pin-prick pain thresholds assessed by weighted-pin instrument (8-512 mN) at primary and secondary hyperalgesia areas (days 1-4).The naloxone-induced unmasking of latent sensitization is an interesting model for exploring the transition from acute to chronic pain. The results from the present study may provide valuable information regarding future research in persistent postsurgical pain states.

Figure 1

General study layout: thermal injuries are induced on day 0 and day 1, and on day 3. Day 0 is a screening day, uncovering low sensitizers [small secondary hyperalgesia areas: lower quartile (Q1)] and high sensitizers [large secondary hyperalgesia areas: upper quartile (Q4)]. Day 1 and day 3 include induction of thermal injuries in high and low sensitizers. Target-controlled-infusion (TCI) days are day 2 and day 4, with randomized allocation between placebo and naloxone. The timeline between day 1 and day 2, and between day 3 and day 4, is 7 days. The timeline between day 0 and day 3 is >8 weeks.

Figure 2

Day 1/day 3 (cf. Fig. 1) includes baseline assessments (green rectangle, 0 minute), induction of a thermal injury (TI, red rectangle, 20 minutes), and postinjury assessments (blue rectangles: 1 hour 27 minutes and 2 hours 27 minutes). Day 2/day 4 (cf. Fig. 1) includes a predrug assessment (magenta rectangle; postinjury 165 hours), drug infusions (naloxone or placebo; 167 hours 35 minutes; 168 hours 0 minute; 168 hours 25 minutes) and assessments during target-controlled infusion [(TCI); grey rectangles]. The estimated TCI plasma concentrations are superimposed in dashed red line. Numbers (1–3) during the infusion period indicate the 3 TCI steps. Timelines for assessments of pin-prick pain thresholds are indicated by red stars, and secondary hyperalgesia areas by green stars.

Figure 3

Test algorithm day 2/day 4 with superimposed naloxone plasma–concentration curves. Median plasma concentration (red) with 10% and 90% percentiles ranged (dashed black lines) during a 3-step target-controlled infusion (TCI). Naloxone is given at step 1 (S1: 15–25 minutes) with 0.25 mg/kg, step 2 (S2: 39–49 minutes) 0.75 mg/kg, and step 3 (S3: 65–75 minutes) 2.25 mg/kg. Yellow timelines represent ratings with Clinical Opiate Withdrawal Scale (COWS) and blue columns indicate sensory testing (BL and S1–3: secondary hyperalgesia areas; BL and S3: pin-prick pain thresholds). BL = baseline assessments (reproduced with permission from trials).^[18]