Importance of non‐pharmacological mechanism of analgesia with spinal puncture

We read the article of Wong et al. entitled ‘Neuraxial Analgesia in Early Labor’ recently published in the New England Journal of Medicine (1) with great interest. In this study, the authors compared the risk of caesarean delivery (primary criteria) and analgesic effects (secondary endpoints) of intrathecal fentanyl (25 mg) vs. hydromorphone when given intramuscularly (1 mg) and intravenously (1 mg) during early labour. While the rate of caesarean delivery was not significantly different between the groups, pain scores were lower, duration of labour was shorter, and Apgar scores were better with intrathecal analgesia. The authors concluded that neuraxial analgesia with fentanyl provides better analgesia than systemic analgesia in early labour. We feel that the study design (1) is not appropriate to draw these conclusions as the authors did not control for the non-specific analgesic effects of spinal puncture. In light of published data and our recent observations, we hypothesize that analgesia reported with ‘neuraxial analgesia’ may be, at least in part, due to effects of psychophysiological stress responses to spinal puncture per se. Pain thresholds inversely correlate with psychophysical responses to stress (2), and an inverse relationship has been demonstrated between sympathetic reactivity, as well as the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and sensitivity to pain (3). Recently, we have analysed the neuroendocrine response to venous and spinal puncture in 10 healthy volunteers aged 28 2.5 years. We measured epinephrine (E), norepinephrine (NE), cortisol, and prolactin (PRL) in plasma, as well as NE and its metabolite 3-methoxy-4-hydroxyphenylglycol (3,4-MHPG) in cerebrospinal fluid (CSF). Blood samples were drawn at three time points: initially after insertion of a 16-G intravenous cannula (cubital vein); then 60 min later (after insertion of a 20-G spinal catheter); and finally 60 min after spinal catherization. Catecholamine concentrations were determined by high-pressure liquid chromatography. Other endocrine variables were detected by the Automated Chemiluminescence-Immunoassay-System 180 (ACS: Centaur, Chiron Diagnostics, Fernwald, Germany). Compared with values obtained after venous puncture, plasma concentrations of epinephrine (E), norepinephrine (NE), cortisol (CORT), and prolactin (PROL) all increased significantly (P < 0.05) immediately after spinal puncture [E: 40.2 7.7 (SE) vs. 44.9 8.4; NE: 293.3 20.4 vs. 344.0 25.5; CORT: 240.6 27.7 vs. 303.4 29.0; PROL: 6.5 0.6 vs. 11.0 2.2] with a subsequent decline of epinephrine and norepinephrine 60 min later (E: 33.2 5.5 pg/ml; NE: 269.9 19.0 pg/ml, P < 0.01 vs. baseline, P < 0.01 vs. immediately after spinal puncture). In parallel, the norepinephrine concentration in CSF was significantly higher after insertion compared with the follow-up measurement 60 min later (84.3 8.1 vs. 73.1 7.6 pg/ml, P < 0.01), whereas CSF concentrations of the norepinephrine metabolite 3,4-MHPG were significantly increased 60 min after lumbar puncture (9.3 0.5 vs. 10.1 0.6, P < 0.01). These neuroendocrine alterations suggest that spinal puncture when compared with venous puncture induces a psychophysiological stress response, which may in turn decrease sensitivity to pain (3), and may explain, at least in part, the analgesic effects of ‘neuraxial analgesia’ during labour. Irrespective of the stress response, spinal puncture may have induced other non-specific treatment effects that provide ‘neuraxial analgesia’. The degree of the analgesic placebo effect (4) is modulated by the extent to which the patient or clinician believe in the effectiveness of a therapy (5). With neuraxial analgesia, we speculate that patients and clinicians may anticipate a more effective analgesic therapy compared with opioid administration via the i.v. and i.m. route, and, thus the analgesic effect of ‘neuraxial analgesia’ may be more profound. Psychophysio-logical stress responses together with non-specific treatment effects may, at least in part, explain the effects of ‘neuraxial analgesia’ on duration of labour, pain scores, and children’s Apgar scores (1). Future studies on the impact of spinal analgesia should control for non-pharmacological analgesic effects of spinal puncture.