Philippe Richebé

An Experimental Paradigm for the Prediction of Post-Operative Pain (PPOP)

Many women undergo cesarean delivery without problems, however some experience significant pain after cesarean section. Pain is associated with negative short-term and long-term effects on the mother. Prior to women undergoing surgery, can we predict who is at risk for developing significant postoperative pain and potentially prevent or minimize its negative consequences? These are the fundamental questions that a team from the University of Washington, Stanford University, the Catholic University in Brussels, Belgium, Santa Joana Womens Hospital in São Paulo, Brazil, and Rambam Medical Center in Israel is currently evaluating in an international research collaboration. The ultimate goal of this project is to provide optimal pain relief during and after cesarean section by offering individualized anesthetic care to women who appear to be more susceptible to pain after surgery. A significant number of women experience moderate or severe acute post-partum pain after vaginal and cesarean deliveries. 1 Furthermore, 10-15% of women suffer chronic persistent pain after cesarean section. 2 With constant increase in cesarean rates in the US 3 and the already high rate in Brazil, this is bound to create a significant public health problem. When questioning womens fears and expectations from cesarean section, pain during and after it is their greatest concern. 4 Individual variability in severity of pain after vaginal or operative delivery is influenced by multiple factors including sensitivity to pain, psychological factors, age, and genetics. The unique birth experience leads to unpredictable requirements for analgesics, from none at all to very high doses of pain medication. Pain after cesarean section is an excellent model to study post-operative pain because it is performed on otherwise young and healthy women. Therefore, it is recommended to attenuate the pain during the acute phase because this may lead to chronic pain disorders. The impact of developing persistent pain is immense, since it may impair not only the ability of women to care for their child in the immediate postpartum period, but also their own well being for a long period of time. In a series of projects, an international research network is currently investigating the effect of pregnancy on pain modulation and ways to predict who will suffer acute severe pain and potentially chronic pain, by using simple pain tests and questionnaires in combination with genetic analysis. A relatively recent approach to investigate pain modulation is via the psychophysical measure of Diffuse Noxious Inhibitory Control (DNIC). This pain-modulating process is the neurophysiological basis for the well-known phenomenon of pain inhibits pain from remote areas of the body. The DNIC paradigm has evolved recently into a clinical tool and simple test and has been shown to be a predictor of post-operative pain.5 Since pregnancy is associated with decreased pain sensitivity and/or enhanced processes of pain modulation, using tests that investigate pain modulation should provide a better understanding of the pathways involved with pregnancy-induced analgesia and may help predict pain outcomes during labor and delivery. For those women delivering by cesarean section, a DNIC test performed prior to surgery along with psychosocial questionnaires and genetic tests should enable one to identify women prone to suffer severe post-cesarean pain and persistent pain. These clinical tests should allow anesthesiologists to offer not only personalized medicine to women with the promise to improve well-being and satisfaction, but also a reduction in the overall cost of perioperative and long term care due to pain and suffering. On a larger scale, these tests that explore pain modulation may become bedside screening tests to predict the development of pain disorders following surgery.

The pneumatic tourniquet: mechanical, ischaemia-reperfusion and systemic effects.

The pneumatic tourniquet is frequently used for upper and lower limb surgery to reduce bleeding, improve visualisation of important structures and expedite surgical procedures. Despite advances in technology, localised tissue damage secondary to cuff compression, ischaemia–reperfusion injuries and systemic complications still occur. The combination of these problems may affect outcome and contribute to prolonged hospitalisation. Use of the correct pneumatic tourniquet cuff size and a patient-specific cuff pressure with careful control of the duration of inflation may help reduce the incidence of these injuries. The efficacy of ischaemic preconditioning or postconditioning, and experimental treatments such as free radical scavenging, and use of nitric oxide synthetase inhibitors on endothelial dysfunction, systemic neutrophil activation and coagulation reactions needs to be established.

Effect of Transversus Abdominis Plane Block With and Without Clonidine on Post–cesarean Delivery Wound Hyperalgesia and Pain

Background and Objectives The transversus abdominis plane (TAP) block is an established technique to manage post–cesarean delivery pain. Transversus abdominis plane blocks with a local anesthetic only offer no analgesic benefits compared with intrathecal morphine. Adjuvants to extend TAP block duration and possibly reduce wound hyperalgesia, known to be a risk factor for chronic pain, have not been studied. We hypothesized that a TAP block with clonidine will affect postsurgical wound hyperalgesia and improve pain outcomes. Methods Ninety women were randomly assigned to receive 1 of 3 TAP blocks after cesarean delivery: saline (placebo), bupivacaine (BupTAP), or bupivacaine + clonidine (CloTAP). The primary outcome was wound hyperalgesia index at 48 hours. Secondary outcomes included pain scores, analgesic consumption, and pain descriptors up to 12 months. Results Wound hyperalgesia index at 48 hours (median [25th–75th percentiles]) was 1.07 (0.48–3.26) in the placebo group, 1.27 (0.59–2.95) in the BupTAP group, and 0.74 (0.09–2.25) in the CloTAP group (P = 0.48). Morphine request in the postanesthesia care unit was significantly higher in the placebo group compared with the other TAP groups (P = 0.01). Postoperative pain scores and requests for breakthrough medication at 48 hours (30% in the placebo group, 24% in the BupTAP group, and 12% in the CloTAP group, P = 0.25) or chronic pain descriptors reported up to 12 months did not differ significantly among groups. Conclusions Adding clonidine to a TAP block with bupivacaine did not affect wound hyperalgesia index and it did not improve short-term or long-term pain scores in women undergoing elective cesarean delivery. Further studies are warranted to determine the benefits of antihyperalgesic adjuvants in TAP solutions for specific individuals at risk for chronic pain.

Transversus abdominis plane catheters for post-cesarean delivery analgesia: a series of five cases.

We present five cases of women who received ultrasound-guided transversus abdominis plane catheters for post-cesarean delivery analgesia. Pain relief was maintained with repeated boluses of local anesthetic combined with oral acetaminophen and ibuprofen unless contraindicated. We conclude that repeated dosing through transversus abdominis plane catheters may be offered to women as an alternative or adjuvant to intrathecal morphine. Larger studies to evaluate the safety and further refinements of this novel procedure are warranted.

Sciatic nerve block fails in preventing the development of late stress-induced hyperalgesia when high-dose fentanyl is administered perioperatively in rats.

Sciatic nerve block fails in preventing the development of late stress-induced hyperalgesia (SIH) when high-dose fentanyl is administered perioperatively in rats. Background and Objectives The aim of our study was to evaluate the effect of regional anesthesia (RA) on hyperalgesia and long-term pain vulnerability after surgery in rats exposed or not to high doses of fentanyl intraoperatively. Methods Experiment 1 evaluated the effects of D 0 RA on hyperalgesia after incision and on the variations of nociceptive threshold (NT) after non-nociceptive environmental stress (NNES) at D 10. Four groups were compared: control K1 (saline in sciatic nerve catheter, no plantar surgery), I (incision: saline in sciatic nerve catheter and plantar surgery), ISSR (incision–single-shot ropivacaine: single-shot ropivacaine, plantar surgery), and IMSR (incision–multiple-shot ropivacaine: 1 shot of ropivacaine, plantar surgery, and then 3 more ropivacaine injections every 2 h). Experiment 2 evaluated the effects of D 0 RA (4 injections) on NT variations after surgery (D 1–D 10) and after stress (D 10) in rats treated with fentanyl at the time of surgery (FI and FIMSR groups). Results Postoperative hyperalgesia lasted for 7, 4, and 2 days for groups I, ISSR, and IMSR, respectively. Non-nociceptive environmental stress at D 10 showed analgesia during stress in K1 (Dunnett, P < 0.05). Poststress area of hyperalgesia showed that I group developed greater hyperalgesia after NNES than ISSR and IMSR did (Mann-Whitney, P < 0.05). In experiment 2 in the FIMSR group, NT was significantly higher at postoperative D 1 and D 2 (Dunnett, P < 0.05), but no difference was shown from D 3 to D 10 (Dunnett, P > 0.05). Hyperalgesic indices calculated for FI and FIMSR groups after NNES at D 10 did no show any significant difference (Dunnett, P > 0.05). Conclusions Perioperative use of long-lasting RA reduced both acute postoperative hyperalgesia and the development of long-term pain vulnerability. However, high doses of fentanyl for intraoperative analgesia induce central sensitization that cannot be reversed by using long-lasting RA.

Preoperative scar hyperalgesia is associated with post-operative pain in women undergoing a repeat Caesarean delivery.

Over 1.4 million Caesarean deliveries are performed annually in the United States, out of which 30% are elective repeat procedures. Post‐operative hyperalgesia is associated with an increased risk for persistent post‐surgical pain; however, there are no data on whether residual scar hyperalgesia (SHA) from a previous Caesarean delivery (CD) persists until the next delivery. We hypothesized that residual SHA may be present in a substantial proportion of women and is associated with increased post‐operative pain.

Perioperative or postoperative nerve block for preventive analgesia: should we care about the timing of our regional anesthesia?

• Volume 116 • Number 5 www.anesthesia-analgesia.org 969 Copyright

Stress-induced hyperalgesia: any clinical relevance for the anesthesiologist?

D URING the last 3 decades, it has been widely reported that intense fear and stress suppress pain. In animals and humans, the typical effect of many stressors was reported as stress-induced analgesia (SIA). However, stress was also reported to exacerbate chronic widespread pain syndromes (e.g., in patients with fibromyalgia). In animals, repeated exposure to stressors (e.g., swim stress, restraint, and social defeat) were shown to produce hyperalgesia. If the mechanisms of SIA have been widely described, those underlying stress-induced hyperalgesia (SIH) remain poorly understood. In the current issue of ANESTHESIOLOGY, Donello et al. report that adrenoceptor-mediated sympathetic efferent mechanisms contribute to SIH. These data bring novel information regarding the effects of psychologic factors in preclinical pain modeling.

Conditioned pain modulation in women with irritable bowel syndrome.

Evidence suggests that patients with irritable bowel syndrome (IBS) are more vigilant to pain-associated stimuli. The aims of this study were to compare women with IBS (n = 20) to healthy control (HC, n = 20) women on pain sensitivity, conditioned pain modulation (CPM) efficiency, and salivary cortisol levels before and after the CPM test and to examine the relationship of CPM efficiency with gastrointestinal pain, somatic pain, psychological distress symptoms, and salivary cortisol levels in each group. Women, aged 20–42 years, gave consent, completed questionnaires, and kept a symptom diary for 2 weeks. CPM efficiency was tested with a heat test stimulus and cold water condition stimulus in a laboratory between 8 and 10 a.m. on a follicular phase day. Salivary cortisol samples were collected just before and after the experimental testing. Compared to the HC group, women with IBS reported more days with gastrointestinal and somatic pain/discomfort, psychological distress, fatigue, and feeling stressed. During the CPM baseline testing, women with IBS reported greater pain sensitivity compared to the HC group. There was no significant group difference in salivary cortisol levels nor in CPM efficiency, though a post-hoc analysis showed a higher prevalence of impaired CPM efficiency among IBS subjects with more severe lower-GI symptoms. In the IBS group, reduced CPM efficiency was associated with daily abdominal pain/discomfort and psychological distress. Overall, women with IBS exhibited an increased sensitivity to thermal stimuli. Impaired CPM was present in a subset of women with IBS.

Intense Focused Ultrasound Preferentially Stimulates Subcutaneous and Focal Neuropathic Tissue: Preliminary Results

OBJECTIVEnPotential peripheral sources of pain from subcutaneous tissue can require invasive evocative tests for their localization and assessment. Here, we describe studies whose ultimate goal is development of a noninvasive evocative test for subcutaneous, painful tissue.nnnDESIGNnWe used a rat model of a focal and subcutaneous neuroma to test the hypothesis that intense focused ultrasound can differentiate focal and subcutaneous neuropathic tissue from control tissue. To do so, we first applied intense focused ultrasound (2u2009MHz, with individual pulses of 0.1 second in duration) to the rats neuroma while the rat was under light anesthesia. We started with low values of intensity, which we increased until intense focused ultrasound stimulation caused the rat to reliably flick its paw. We then applied that same intense focused ultrasound protocol to control tissue away from the neuroma and assayed for the rats response to that stimulation.nnnRESULTSnIntense focused ultrasound of sufficient strength (I(SATA) of 600 +/- 160u2009W/cm(2) ) applied to the neuroma caused the rat to flick its paw, while the same intense focused ultrasound applied millimeters to a centimeter away failed to induce a paw flick.nnnCONCLUSIONnSuccessful stimulation of the neuroma by intense focused ultrasound required colocalization of the neuroma and intense focused ultrasound supporting our hypothesis.