Experimental pain and opioid analgesia in volunteers at high risk for obstructive sleep apnea

Abstract

Background: Obstructive sleep apnea (OSA) is characterized by recurrent nocturnal hypoxia and sleep disruption. Sleep fragmentation caused hyperalgesia in volunteers, while nocturnal hypoxemia enhanced morphine analgesic potency in children with OSA. This evidence directly relates to surgical OSA patients who are at risk for airway compromise due to postoperative use of opioids. Using accepted experimental pain models, we characterized pain processing and opioid analgesia in male volunteers recruited based on their risk for OSA.

Methods: After approval from the Intitutional Review Board and informed consent, we assessed heat and cold pain thresholds and tolerances in volunteers after overnight polysomnography (PSG). Three pro-inflammatory and 3 hypoxia markers were determined in the serum. Pain tests were performed at baseline, placebo, and two effect site concentrations of remifentanil (1 and 2 µg/ml), an μ-opioid agonist. Linear mixed effects regression models were employed to evaluate the association of 3 PSG descriptors [wake after sleep onset, number of sleep stage shifts, and lowest oxyhemoglobin saturation (SaO(2)) during sleep] and all serum markers with pain thresholds and tolerances at baseline, as well as their changes under remifentanil.

Results: Forty-three volunteers (12 normal and 31 with a PSG-based diagnosis of OSA) were included in the analysis. The lower nadir SaO(2) and higher insulin growth factor binding protein-1 (IGFBP-1) were associated with higher analgesic sensitivity to remifentanil (SaO(2), P = 0.0440; IGFBP-1, P = 0.0013). Other pro-inflammatory mediators like interleukin-1β and tumor necrosis factor-α (TNF-α) were associated with an enhanced sensitivity to the opioid analgesic effect (IL-1β, P = 0.0218; TNF-α, P = 0.0276).

Conclusions: Nocturnal hypoxemia in subjects at high risk for OSA was associated with an increased potency of opioid analgesia. A serum hypoxia marker (IGFBP-1) was associated with hypoalgesia and increased potency to opioid analgesia; other pro-inflammatory mediators also predicted an enhanced opioid potency.

Trial registration: Clinicaltrials.gov NCT00672737.

Figure 1. Study flow scheme.

On the first study day, the volunteers underwent home-based or in-hospital overnight polysomnography (PSG). Approximately a week later, they underwent experimental pain testing after a blood sample was withdrawn for determination of pro-inflammatory and hypoxia markers. Threshold and tolerances were determined for both heat and cold painful stimuli at baseline (no drug), placebo, and two (low and high) effect site concentrations (Ce) of remifentanil (1 and 2 µg/ml, or 2 and 4 µg/ml) that were targeted using an electronic syringe pump connected to a laptop equiped with a special software driver (STANPUMP, written by Steve L. Shafer, MD) and a pharmacokinetic-pharmacodynamic model for remifentanil. The order of presentation for the two remifentanil Ce was randomized, using special software and sealed envelopes that were opened on the day of trial.

Figure 2. Volunteers and study procedures.

A total of 167 volunteers were screened via telephone or a personal interview. Fifty six volunteers signed an informed concent; 3 of them withdrew before participation in any of the study procedures. All remaining 53 underwent an overnight polysomnography, but only 49 came for the pain test on the second study day. Blood was not drawn from 3 volunteers due to technical difficulties, while 2 more blood samples were lost before analysis was done; a total of 44 blood samples provided data on inflammatory and hypoxia markers. The first 9 volunteers were tested on remifentanil Ce of 2 and 4 µg/ml and all the remaining on 1 and 2 µg/ml. Two volunteers experienced intence nausea; one at the end and the other at the beginning of the first remifentanil Ce (2 µg/ml); the experiment was stopped in both cases, but pain-related measurements were acquired only in the first case. A pump malfunction prohibited the administration of remifentanil in 1 subject. One volunteer was excluded from the analysis due to an inadequate sleep study. Finally, data from 48 volunteers were included in the analysis.