Three days after surgery, no significant differences in detection thresholds were found between the groups (warm median °C [IQR] 30.2 [29.6 to 30.7] vs. 29.8 [28.6 to 30.7] P = 0.320; cold: 35.2 [34.6 to 36.5] vs. 35.7 [34.6 to 36.9], P = 0.31). Pain thresholds were not significantly different between groups (heat pain median °C [IQR] 47.0 [44.2 to 48.6] vs. 46.8 [43.7 to 49.0], P = 0.87; cold pain median °C [IQR] 10.1 [2.8 to 18.4] vs. 8.6 [1.3 to 20.1], P = 0.86). Twelve months after surgery, no significant differences in detection and pain thresholds (median °C [IQR]) were found between the groups (warm detection: 35.2 [34.5 to 36.3] vs. 35.3 [34.5 to 36.9], P = 0.91; cold detection: 30.4 [29.4 to 30.7] vs. 30.3 [29.5 to 30.7], P = 0.70; heat pain: 47.7 [45.4 to 49.2] vs. 48.1 [45.7 to 49.4], P = 0.88; cold pain: 6.6 [1.7 to 18.3] vs. 4.8 [1.6 to 13.5], P = 0.65) (Fig. 2).
Independent of group allocation, three days after surgery pain thresholds for heat and cold (median °C [IQR]) were lower than baseline values (heat: 46.9 [43.8 to 48.7] vs. 48.1 [46.4 to 49.1], P < 0.001; cold: 9.5 [1.8 to 19.2] vs. 5.6 [1.5 to 15.3]; P = 0.002). This could not be explained by the reaction time, as this was significantly higher 3 days postsurgery compared with baseline (0.308 ± 0.1 vs. 0.380 ± 0.1; P < 0.001). Pain thresholds returned back to baseline levels 12 months after surgery (heat baseline: 48.1 [46.4 to 49.1] vs. 12 months: 48.0 [45.7 to 49.3], P = 0.782; cold baseline: 5.7 [1.5 to 15.2] vs. 12 months: 4.9 [1.7 to 15.5], P = 0.588) (Supplemental data content Table S1, http://links.lww.com/EJA/A173).
Twelve months after surgery, detection thresholds for heat and cold (median °C [IQR]) were lower than baseline values (heat: 35.2 [34.5 to 36.4] vs. 35.8 [34.7 to 37.3]; P = 0.047; cold: 30.4 [29.4 to 30.7] vs. 29.9 [28.9 to 30.6]; P = 0.045) (Supplemental data content Table S1, http://links.lww.com/EJA/A173).
Regression estimates for the four QST modalities measured 12 months after surgery are shown in Table 2. In the model, treatment condition (remifentanil or fentanyl), presence of chronic pain 12 months after surgery, age, opioid consumption and pre-operative QoL were not significantly associated with altered pain sensitivity measured with QST. Baseline values were associated with the follow-up values for cold detection and pain thresholds 12 months after surgery. The regression estimates for detection and pain thresholds measured 3 days after surgery also revealed no significant predictors for altered pain sensitivity. For all four modalities, baseline measurements showed significant correlation with the measurement 3 days after surgery after adjustment for other variables (Supplemental data content Table S2, http://links.lww.com/EJA/A173).
Several studies of widely different design found that remifentanil use during surgery correlated with more postoperative pain and higher opioid consumption in the short term. 16,18 The aim of this study was to determine whether the intra-operative use of remifentanil would have any effect on thermal detection and pain thresholds in the short and longer term after surgery. Statistical analysis showed no significant differences in detection and pain thresholds in patients treated with remifentanil or fentanyl 3 days and 1 year after cardiac surgery. In a regression analysis, no other significant predictors for altered pain sensitivity 1 year after surgery were present.
The primary analysis of the REFLECT trial showed that patients receiving remifentanil during cardiac surgery needed more opioids after surgery to reach adequately low pain scores. In addition, 3 months after surgery, these patients also reported more pain related to the surgery, a difference that was not found 1 year after surgery. 20 These potential short-term effects of remifentanil did not result in significant differences in pain and detection thresholds 3 days after surgery. In line with the reported pain scores, sensory thresholds 1 year after surgery were also not significantly different between the two groups.
Regarding the effect of remifentanil on QST modalities directly after surgery, one study showed an increase in pain sensitivity to tactile stimuli in the high-dose remifentanil group during 2 days after surgery. 29 Another study found a decrease in pressure pain tolerance thresholds directly after eye surgery in the high-dose remifentanil group, whereas thermal thresholds showed no effect. 30 In the current study, thermal pain thresholds 3 days after surgery had significantly decreased from baseline values in both treatment groups. This could indicate higher sensitivity for heat and cold sensation 3 days after the surgery, despite the administration of analgesics. A confounding factor is that patients in the remifentanil group received more opioids in the first 48 h compared with the fentanyl group. However, patients in both groups had received opioids and decreased thresholds were found in both groups. One year after surgery, pain thresholds had returned to baseline values. No significant differences in detection and pain thresholds were found between the remifentanil and fentanyl groups.
To our knowledge, no data is available regarding the intra-operative use of remifentanil and its effect on hyperalgesia measured with QST in the longer term. Despite being another concept than hyperalgesia, with different definition and mechanism, one study measured allodynia (i.e. pain due to a stimulus that does not usually provoke pain) 1 month after remifentanil administration. In 38 cardiac surgery patients, an increased area of mechanical allodynia around the incisional site was found in the patients receiving high dose remifentanil and postsurgical epidural analgesia. 31 This study illustrates that remifentanil use during surgery can have an impact on sensory thresholds in the longer term. Our study assessed only secondary hyperalgesia, which is thought to derive from central sensitisation to pain. 32 No differences in thermal thresholds were found before and 12 months after surgery. As patients in the remifentanil group directly after surgery had an increased need for opioids and reported more thoracic pain 3 months after surgery, it was encouraging to find that after 12 months there were no significant differences in patient-reported outcomes or in sensory thresholds. This implies that the clinical relevance of remifentanil-induced (secondary) hyperalgesia on sensory perception in the longer term is minimal or possibly self-limiting.
The possible mechanisms of remifentanil-induced hyperalgesia are still controversial. The ultrashort half-life of remifentanil together with inadequate and timely administration of long-acting analgesics could be an explanation for the increase in pain scores and in the use of postoperative opioids after the use of remifentanil. However, in our and other studies in which long-acting opioids were administered in a timely manner for bridging the possible opioid gap, increases in pain parameters directly after surgery have been reported. 17,18 This suggests that there are more potential causes of hyperalgesia.
On a molecular level, it has been suggested that changes in neuroplasticity in the peripheral and central nervous system may lead to central sensitisation of nociceptive pathways, resulting in reduced nociceptive thresholds. 33 Although multiple mechanisms are postulated, the N-methyl-D-aspartate (NMDA) receptor appears to play a key role in the development of opioid-induced hyperalgesia. This receptor is involved in neuroplasticity and long-term potentiation, and affected by remifentanil through multiple pathways. 34–36 It is unknown what the mechanism is regarding a prolonged remifentanil effect, but animal data showed a potential role of protein kinase C zeta (PRCKZ), which appears to plays a role in the development of prolonged remifentanil-induced hyperalgesia. PRCKZ is involved in long-term potentiation and pain memory, peaks 2 days after cessation of remifentanil infusion and returns to baseline level after 7 days. Blockade of this substance reversed postinfusion hyperalgesia induced by remifentanil. 37 The involvement of the NMDA receptor and its role in neuroplasticity could possibly explain the transient negative impact of remifentanil 3 months after surgery. This is only hypothesising, and more research is needed to identify the complex pathways that are involved in the acute and prolonged effects of remifentanil.
The reported incidence of chronic thoracic pain 1 year after surgery in this study is 18.9% overall and not significantly different between study groups. Previous studies have reported 1-year incidences around 25%. 2–4 Pharmacological interventions for preventing chronic pain are still not convincing, with a modest effect of ketamine as most promising. 38 Other drugs, for example pregabalin, seem to have no added value. 39
QST is widely used to diagnose and monitor chronic and neuropathic pain disorders. 11 However, in routine clinical practice, QST is not well established in relation to postoperative pain because results are conflicting or not convincing, and measurements are time-consuming. As mentioned above, some studies report a predictive value of pre-operative QST measurements, whereas others find no such association. 40,41 Our study shows no distinctive added value of measuring thermal detection and pain thresholds for evaluating chronic postsurgical pain in patients 1 year after cardiac surgery. In addition to thermal thresholds, other methods have been used to study chronic postoperative pain. Measurement of diffuse inhibitory noxious control (DNIC) gives a dynamic view of the pain processing system. 42 Patients with impaired conditioned pain modulation or DNIC were found to have a greater likelihood of developing chronic postoperative pain. 11,43 Pre-operative DNIC explained around 25% of the variability in chronic postoperative pain intensity, whereas the numbers of static thresholds were below 6%. It is possible that the use of multiple modalities of QST, such as pressure, electrical thresholds or measuring DNIC, provides more information, but the more extensive and time-consuming, the more difficult is the use of QST protocols in daily practice. In addition, static QST thresholds such as detection and pain thresholds appear to have sufficient test–retest reliability. 44 Our study measured thermal detection and pain thresholds 3 days and 12 months after surgery and was performed to assess the potential of QST for application in clinical practice. After all, it takes only 16 to 18 min per measurement. Still, gathering pieces of evidence of the complicated puzzle of postoperative pain management adds to the final goal of reducing incidences of short-term and chronic postoperative pains. Recently, it has been suggested that patients with peripheral neuropathic pain can be divided into subgroups on the basis of sensory profiles, potentially increasing the response to pharmacological treatment. 45 Whether QST can also play a role in the management of postoperative pain is a field for future research.
First, the ideal study design should be double-blind and contain no other opioid besides remifentanil. Patients in the remifentanil group also received fentanyl during surgery as this was standard care in our hospital and it is not, in our opinion, in patients’ best interest to use a high-dose remifentanil as the single analgesic during this prolonged procedure because of the risk of increased immediate postoperative pain. Of note, an earlier observational study using the same regimens suggested that remifentanil was predictive for chronic thoracic pain 1 year after the study. 19 However, it has to be taken into account that patients in the remifentanil group also received fentanyl during surgery and the possibility that fentanyl does not contribute to the outcome of this study cannot be excluded.
Second, the design of this study is single-blind. In our opinion, blinding only patients to study treatment was enough to ensure a valid outcome of the primary and secondary outcomes because patients self-reported pain scores and were in control of QST measurements.
Third, the QST-battery was limited to thermal stimuli, whereas multiple modalities (e.g. electrical, pressure) can give more information about pain perception of the individual patient. Conclusions can be drawn only for the development of secondary hyperalgesia 1 year after remifentanil administration measured with thermal thresholds. For instance, no data are available about mechanical or electrical tests around the wound.
Despite the unfavourable effects of remifentanil vs. fentanyl on chronic thoracic pain after 3 months, it is positive that no significant effect of remifentanil on thermal pain sensitivity and chronic thoracic pain was found 1 year after cardiac surgery. Additional predictors of altered pain sensitivity could not be identified. Again, this study contributes to the body of literature that concludes that chronic postoperative pain is multimodal and it remains difficult to predict which patients are at risk for chronic postoperative pain. However, this study showed again a high incidence of chronic thoracic pain after cardiac surgery, which is known to have a considerable impact on QoL. Investing in the prevention and early detection of chronic postsurgical pain is the next logical step.
Acknowledgements relating to this article
Assistance with the study: the authors thank Richard Sandifort, BSc, Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, The Netherlands for support in data entry and Ko Hagoort, MA, Department of Paediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, the Netherlands for text editing.
Financial support and sponsorship: support was provided solely from institutional and/or departmental sources.
Conflicts of interest: none.
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© 2019 European Society of Anaesthesiology