High-dose naloxone: Effects by late administration on pain and hyperalgesia following a human heat injury model. A randomized, double-blind, placebo-controlled, crossover trial with an enriched enrollment design

Abstract

Severe chronic postsurgical pain has a prevalence of 4-10% in the surgical population. The underlying nociceptive mechanisms have not been well characterized. Following the late resolution phase of an inflammatory injury, high-dose μ-opioid-receptor inverse agonists reinstate hypersensitivity to nociceptive stimuli. This unmasking of latent pain sensitization has been a consistent finding in rodents while only observed in a limited number of human volunteers. Latent sensitization could be a potential triggering venue in chronic postsurgical pain. The objective of the present trial was in detail to examine the association between injury-induced secondary hyperalgesia and naloxone-induced unmasking of latent sensitization. Healthy volunteers (n = 80) received a cutaneous heat injury (47°C, 420 s, 12.5 cm2). Baseline secondary hyperalgesia areas were assessed 1 h post-injury. Utilizing an enriched enrollment design, subjects with a magnitude of secondary hyperalgesia areas in the upper quartile ('high-sensitizers' [n = 20]) and the lower quartile ('low-sensitizers' [n = 20]) were selected for further study. In four consecutive experimental sessions (Sessions 1 to 4), the subjects at two sessions (Sessions 1 and 3) received a cutaneous heat injury followed 168 h later (Sessions 2 and 4) by a three-step target-controlled intravenous infusion of naloxone (3.25 mg/kg), or normal saline. Assessments of secondary hyperalgesia areas were made immediately before and stepwise during the infusions. Simple univariate statistics revealed no significant differences in secondary hyperalgesia areas between naloxone and placebo treatments (P = 0.215), or between 'high-sensitizers' and 'low-sensitizers' (P = 0.757). In a mixed-effects model, secondary hyperalgesia areas were significantly larger following naloxone as compared to placebo for 'high-sensitizers' (P < 0.001), but not 'low-sensitizers' (P = 0.651). Although we could not unequivocally demonstrate naloxone-induced reinstatement of heat injury-induced hyperalgesia, further studies in clinical postsurgical pain models are warranted.

Fig 1. CONSORT flow diagram.

A total of 170 individuals replied to the advertisement. Ninety-four subjects were assessed for general eligibility on an enrichment selection session (Session 0). Twelve subjects were excluded before the assessments, three tested positive for tetrahydrocannabinol (THC) in their urine, one used prescription drugs and seven had scars or tattoos in the assessment areas. Eighty-three subjects received a cutaneous heat injury (CHI) on Session 0. Subsequently, three subjects were excluded, two subjects did not develop secondary hyperalgesia areas (SHAs), and one subject had a vasovagal syncope following the CHI. Eighty subjects’ SHAs were analyzed and ranked according to magnitude, assessed by planimetric measurements. Through an enrichment process, 40 subjects with SHAs in the two middle quartiles (Q2/Q3) were discontinued, while the 20 subjects belonging to the lower quartile (Q1) and the 20 subjects belonging to the upper quartile (Q4) were randomized and continued to the experimental sessions. Two subjects from Q4 were, however, excluded before the allocation procedure in Session 1 for reasons unrelated to the trial, one subject was unavailable, and another was diagnosed with acute lymphocytic leukemia (ALL). All other subjects completed per-protocol the trial sessions, and the final analysis, thus, included 38 subjects.

Fig 2. General trial layout.

Cutaneous heat injuries were induced on an enrichment session (Session 0), a selection process uncovering ‘high-sensitizers’ (large secondary hyperalgesia areas: upper quartile [Q4]) and ‘low-sensitizers’ (small secondary hyperalgesia areas: lower quartile [Q1]). Sessions 1 and 3 included repeat cutaneous heat injuries in ‘high- and low-sensitizers’. Target-controlled infusion sessions were Sessions 2 and 4, with randomized allocation between placebo and naloxone. The time interval between Sessions 1 and 2, and, Sessions 3 and 4, was 7 days. The time interval between Sessions 0 and 3 was > 8 weeks.

Fig 3. Trial timeline.

Session 1 and 3 (cf. Fig 1) included baseline assessments (green rectangle, 0 min), induction of a cutaneous heat injury (CHI, red rectangle, 20 min) and post-injury assessments (blue rectangles: 1 h 27 min and 2 h 27 min). Session 2 and 4 (cf. Fig 1) included a pre-drug assessment (magenta rectangle; post-injury 165 h), drug-infusions (naloxone or placebo; 167 h 35 min, 168 h 0 min, and 168 h 25 min), and assessments during target-controlled infusion (TCI; grey rectangles; 167 h 35 min, 168 h 0 min, and 168 h 25 min). The estimated TCI plasma concentrations are superimposed in dashed red line. Numbers (1 to 3) during the infusion period, indicate the three TCI-steps. Assessments included secondary hyperalgesia areas and online reaction time indicated by green stars and pin-prick pain thresholds indicated by red stars.

Fig 4. Target-controlled infusion.

Test-algorithm Session 2 and 4 for subjects with superimposed naloxone plasma-concentration curves. Median plasma-concentration (red) with 10% and 90% percentiles ranges (dashed black lines) during a three-step target-controlled infusion (TCI). Naloxone was administered at step 1 (ST1: 15 min to 25 min) with 0.25 mg/kg, step 2 (ST2: 39 min to 49 min) 0.75 mg/kg, and step 3 (ST3: 65 min to 75 min) 2.25 mg/kg. Magenta columns represent ratings with Clinical Opiate Withdrawal Scale (COWS) and blue columns indicate sensory testing (BL and ST1 to ST3: secondary hyperalgesia areas; BL and ST3: pin-prick pain thresholds). BL: baseline assessments [22].

Fig 5. Sensitizer categorization following cutaneous heat injuries.

Secondary hyperalgesia areas as measured at baseline on Sessions 0, 1, and 3. Red lines illustrate ‘high-sensitizers’ and blue lines illustrate ‘low-sensitizers’. The blue rectangle shows the Q1 interval and the red rectangle shows the Q4 interval as defined on Session 0.

Fig 6. Magnitude of secondary hyperalgesia areas following naloxone or placebo.

Comparison of individual maximum secondary hyperalgesia area (SHA_MAX) with subtraction of baseline areas after administration of naloxone or placebo. When all subjects were analyzed without partitioning into ‘high- and low-sensitizers’, there were no significant difference between SHAs following naloxone infusion (median [95% CI]: 0 [0–0.3] cm²), compared to the placebo infusion (median [95% CI]: 0 [0–0] cm²; Wilcoxon signed-rank test: P = 0.215). Furthermore, no significant difference for SHA_MAX was found between ‘high-sensitizers’ (median [95% CI]: 0 [0–14.4] cm²) and ‘low-sensitizers’ (median [95% CI]: 0 [0–0] cm²; Mann-Whitney U test: P = 0.757). Red lines represent ‘high-sensitizers’ and blue lines represent ‘low-sensitizers’.