Patricia Lavand'homme

'Balanced analgesia' in the perioperative period : Is there a place for ketamine?

&NA; We investigated whether intraoperative ‘subanesthetic doses’ of ketamine have a postoperative anti‐hyperalgesic and an analgesic effect and which is the preferential route of administration, either systemic (intravenous, i.v.) or epidural. One hundred patients scheduled for rectal adenocarcinoma surgery under combined epidural/general anesthesia were included. Before skin incision all the patients received an epidural bolus followed by an infusion of continuous bupivacaine/sufentanil/clonidine mixture. They were randomly assigned to receive no ketamine (group 1), i.v. ketamine at the bolus dose of 0.25 mg/kg followed by an infusion of 0.125 mg/kg per h (group 2), 0.5 mg/kg and 0.25 mg/kg per h (group 3), epidural ketamine 0.25 mg/kg and 0.125 mg/kg per h (group 4), or 0.5 mg/kg and 0.25 mg/kg per h (group 5). All i.v. and epidural analgesics were stopped at the end of surgery and patients were connected to an i.v. morphine patient‐controlled analgesia (PCA) device. Short‐term postoperative analgesia (72 h) was assessed by pain visual analog scale scores at rest, cough, and movements as well as by PCA requirements. Wound mechanical hyperalgesia was evaluated and residual pain was assessed by asking the patients at 2 weeks, and 1, 6, and 12 months. The area of hyperalgesia and morphine PCA requirements were significantly reduced in group 3. These patients reported significantly less residual pain until the sixth postoperative month. These observations support the theory that subanesthetic doses of i.v. ketamine (0.5 mg/kg bolus followed by 0.25 mg/kg per h) given during anesthesia reduce wound hyperalgesia and are a useful adjuvant in perioperative balanced analgesia. Moreover, they show that the systemic route clearly is the preferential route.

Intraoperative Epidural Analgesia Combined with Ketamine Provides Effective Preventive Analgesia in Patients Undergoing Major Digestive Surgery

Background: As a broader definition of preemptive analgesia, preventive analgesia aims to prevent the sensitization of central nervous system, hence the development of pathologic pain after tissular injury. To demonstrate benefits from preventive treatment, objective measurement of postoperative pain such as wound hyperalgesia and persistent pain should be evaluated. The current study assessed the role and timing of epidural analgesia in this context. Methods: In a randomized, double-blinded trial, 85 patients scheduled to undergo neoplastic colonic resection were included. All the patients received a thoracic epidural catheter, systemic ketamine at a antihyperalgesic dose, and general anesthesia. Continuous infusion of analgesics belonging to the same class was administered by either intravenous or epidural route before incision until 72 h after surgery. Patients were allocated to four groups to receive intraoperative intravenous lidocaine–sufentanil–clonidine or epidural bupivacaine–sufentanil–clonidine followed postoperatively by either intravenous (lidocaine–morphine–clonidine) or epidural (bupivacaine–sufentanil–clonidine) patient-controlled analgesia. Postoperative pain scores (visual analog scale), analgesic consumption, wound area of punctuate hyperalgesia, residual pain, and analgesics needed from 2 weeks until 12 months were recorded. Results: Analgesic requirements, visual analog scale scores, and area of hyperalgesia were significantly higher in the intravenous treatment group (intravenous–intravenous), and more patients reported residual pain from 2 weeks until 1 yr (28%). Although postoperative pain measurements did not differ, postoperative epidural treatment (intravenous–epidural) was less effective to prevent residual pain at 1 yr (11%; P = 0.2 with intravenous–intravenous group) than intraoperative one (epidural–epidural and epidural–intravenous groups) (0%; P = 0.01 with intravenous–intravenous group). Conclusion: Combined with an antihyperalgesic dose of ketamine, intraoperative epidural analgesia provides effective preventive analgesia after major digestive surgery.

A classification of chronic pain for ICD-11

Chronic pain has been recognized as pain that persists past normal healing time5 and hence lacks the acute warning function of physiological nociception.35 Usually pain is regarded as chronic when it lasts or recurs for more than 3 to 6 months.29 Chronic pain is a frequent condition, affecting an estimated 20% of people worldwide6,13,14,18 and accounting for 15% to 20% of physician visits.25,28 Chronic pain should receive greater attention as a global health priority because adequate pain treatment is a human right, and it is the duty of any health care system to provide it.4,13 The current version of the International Classification of Diseases (ICD) of the World Health Organization (WHO) includes some diagnostic codes for chronic pain conditions, but these diagnoses do not reflect the actual epidemiology of chronic pain, nor are they categorized in a systematic manner. The ICD is the preeminent tool for coding diagnoses and documenting investigations or therapeutic measures within the health care systems of many countries. In addition, ICD codes are commonly used to report target diseases and comorbidities of participants in clinical research. Consequently, the current lack of adequate coding in the ICD makes the acquisition of accurate epidemiological data related to chronic pain difficult, prevents adequate billing for health care expenses related to pain treatment, and hinders the development and implementation of new therapies.10,11,16,23,27,31,37 Responding to these shortcomings, the International Association for the Study of Pain (IASP) contacted the WHO and established a Task Force for the Classification of Chronic Pain. The IASP Task Force, which comprises pain experts from across the globe,19 has developed a new and pragmatic classification of chronic pain for the upcoming 11th revision of the ICD. The goal is to create a classification system that is applicable in primary care and in clinical settings for specialized pain management. A major challenge in this process was finding a rational principle of classification that suits the different types of chronic pain and fits into the general ICD-11 framework. Pain categories are variably defined based on the perceived location (headache), etiology (cancer pain), or the primarily affected anatomical system (neuropathic pain). Some diagnoses of pain defy these classification principles (fibromyalgia). This problem is not unique to the classification of pain, but exists throughout the ICD. The IASP Task Force decided to give first priority to pain etiology, followed by underlying pathophysiological mechanisms, and finally the body site. Developing this multilayered classification was greatly facilitated by a novel principle of assigning diagnostic codes in ICD-11, termed “multiple parenting.” Multiple parenting allows the same diagnosis to be subsumed under more than 1 category (for a glossary of ICD terms refer to Table ​Table1).1). Each diagnosis retains 1 category as primary parent, but is cross-referenced to other categories that function as secondary parents. Table 1 Glossary of ICD-11 terms. The new ICD category for “Chronic Pain” comprises the most common clinically relevant disorders. These disorders were divided into 7 groups (Fig. ​(Fig.1):1): (1) chronic primary pain, (2) chronic cancer pain, (3) chronic posttraumatic and postsurgical pain, (4) chronic neuropathic pain, (5) chronic headache and orofacial pain, (6) chronic visceral pain, and (7) chronic musculoskeletal pain. Experts assigned to each group are responsible for the definition of diagnostic criteria and the selection of the diagnoses to be included under these subcategories of chronic pain. Thanks to Bedirhan Ustun and Robert Jakob of the WHO, these pain diagnoses are now integrated in the beta version of ICD-11 (http://id.who.int/icd/entity/1581976053). The Task Force is generating content models for single entities to describe their clinical characteristics. After peer review overseen by the WHO Steering Committee,39 the classification of chronic pain will be voted into action by the World Health Assembly in 2017. Figure 1 Organizational chart of Task Force, IASP, and WHO interactions. The IASP Task Force was created by the IASP council and its scope defined in direct consultation of the chairs (R.D.T. and W.R.) with WHO representatives in 2012. The Task Force reports to ... 2. Classification of chronic pain Chronic pain was defined as persistent or recurrent pain lasting longer than 3 months. This definition according to pain duration has the advantage that it is clear and operationalized. Optional specifiers for each diagnosis record evidence of psychosocial factors and the severity of the pain. Pain severity can be graded based on pain intensity, pain-related distress, and functional impairment. 2.1. Chronic primary pain Chronic primary pain is pain in 1 or more anatomic regions that persists or recurs for longer than 3 months and is associated with significant emotional distress or significant functional disability (interference with activities of daily life and participation in social roles) and that cannot be better explained by another chronic pain condition. This is a new phenomenological definition, created because the etiology is unknown for many forms of chronic pain. Common conditions such as, eg, back pain that is neither identified as musculoskeletal or neuropathic pain, chronic widespread pain, fibromyalgia, and irritable bowel syndrome will be found in this section and biological findings contributing to the pain problem may or may not be present. The term “primary pain” was chosen in close liaison with the ICD-11 revision committee, who felt this was the most widely acceptable term, in particular, from a nonspecialist perspective.

severity of acute pain after childbirth, but not type of delivery, predicts persistent pain and postpartum depression

Abstract Cesarean delivery rates continue to increase, and surgery is associated with chronic pain, often co‐existing with depression. Also, acute pain in the days after surgery is a strong predictor of chronic pain. Here we tested if mode of delivery or acute pain played a role in persistent pain and depression after childbirth. In this multicenter, prospective, longitudinal cohort study, 1288 women hospitalized for cesarean or vaginal delivery were enrolled. Data were obtained from patient interviews and medical record review within 36 h postpartum, then via telephone interviews 8 weeks later to assess persistent pain and postpartum depressive symptoms. The impact of delivery mode on acute postpartum pain, persistent pain and depressive symptoms and their interrelationships was assessed using regression analysis with propensity adjustment. The prevalence of severe acute pain within 36 h postpartum was 10.9%, while persistent pain and depression at 8 weeks postpartum were 9.8% and 11.2%, respectively. Severity of acute postpartum pain, but not mode of delivery, was independently related to the risk of persistent postpartum pain and depression. Women with severe acute postpartum pain had a 2.5‐fold increased risk of persistent pain and a 3.0‐fold increased risk of postpartum depression compared to those with mild postpartum pain. In summary, cesarean delivery does not increase the risk of persistent pain and postpartum depression. In contrast, the severity of the acute pain response to childbirth predicts persistent morbidity, suggesting the need to more carefully address pain treatment in the days following childbirth.

The comparative toxicity of ropivacaine and bupivacaine at equipotent doses in rats.

We compared the toxicity of systemic local anesthetics bupivacaine and ropivacaine administered at equivalent and equipotent doses. In the first experiments, 18 male Wistar rats were anesthetized with thiopental and maintained under positive controlled ventilation. Electrocardiogram, electroencephalogram, and invasive arterial blood pressure were continuously recorded. The animals were randomly assigned to receive 3 mg · kg−1 · min−1 bupivacaine, 3 mg · kg−1 · min−1 ropivacaine IV (equivalent group), or 4.5 mg · kg−1 · min−1 ropivacaine (equipotent group). The timing of the occurrence of local anesthetic-induced toxic events (defined as the first QRS modification, dysrhythmia, seizures, moderate and severe bradycardia and hypotension, final systole) was recorded and the dose calculated. Eighteen additional rats, treated according to the same protocol were killed at the time of moderate, severe, and final hypotension for blood sampling and plasma bupivacaine and ropivacaine concentration measurement. In a third experiment, 15 awake rats (5 per group) received IV bupivacaine or ropivacaine (same infusion as in the first experiments) until seizure. At this moment, rats were allowed to recover from local anesthetic intoxication. In the first experiment, except for the first QRS modification, all the other toxic manifestations occurred at significantly larger doses (P < 0.05) in the two ropivacaine groups in comparison to the bupivacaine group. In awake rats, all the animals intoxicated by ropivacaine easily recovered. In the bupivacaine group, two animals required cardiopulmonary resuscitation before any seizure activity could be detected, and only three rats survived. We conclude that, in the model used, ropivacaine, even at an equipotent dose, is less toxic than bupivacaine. Implications Our results clearly demonstrate that ropivacaine, even used at an equipotent dose, has a wider therapeutic index than bupivacaine.

Postoperative analgesic effects of continuous wound infiltration with diclofenac after elective cesarean delivery.

Background:Postoperative pain mostly results from sensitization of afferent fibers at injury sites driving central sensitization. Recently, peripheral processes have gained attention as mechanisms of hyperalgesia, and prostaglandins are among highly sensitizing agents. To date, perioperative administration of a single local dose of nonsteroidal antiinflammatory drugs has shown inconclusive efficacy. Rather than a single bolus, the current study evaluates the postoperative analgesic effect of diclofenac continuous intrawound infusion after elective cesarean delivery. Methods:Ninety-two parturients were randomly allocated to receive a 48-h continuous intrawound infusion with 240 ml containing 300 mg diclofenac, 0.2% ropivacaine, or saline. In the ropivacaine and saline groups, patients also received 75 mg intravenous diclofenac every 12 h for 48 h. Postoperative evaluation included intravenous morphine consumption by patient-controlled analgesia and visual analog pain scores. Punctate mechanical hyperalgesia surrounding the wound and presence of residual pain after 1 and 6 months were also assessed. Results:Continuous diclofenac infusion significantly reduced postoperative morphine consumption (18 mg; 95% confidence interval, 12.7–22.2) in comparison with saline infusion and systemic diclofenac (38 mg; 95% confidence interval, 28.8–43.7) (P = 0.0009) without unique adverse effects. Postoperative analgesia produced by local diclofenac infusion was as effective as local ropivacaine infusion with systemic diclofenac. Conclusions:After elective cesarean delivery, continuous intrawound infusion of diclofenac demonstrates a greater opioid-sparing effect and better postoperative analgesia than the same dose administered as an intermittent intravenous bolus.

Perioperative administration of the α2-adrenoceptor agonist clonidine at the site of nerve injury reduces the development of mechanical hypersensitivity and modulates local cytokine expression

The development of chronic pain after surgery is not rare. Nerve injury from complete or partial nerve section during surgery leads to macrophage recruitment and release of pro‐inflammatory cytokines, leading in turn to sensitization. Macrophages also express &agr;2‐adrenoceptors, and we previously demonstrated a prolonged reduction in hypersensitivity following peri‐neural injection of the &agr;2‐adrenoceptor agonist, clonidine, in rats with chronic nerve injury. The current study tested whether peri‐neural clonidine at the time of injury could also prevent development of hypersensitivity. Rats underwent partial ligation of one sciatic nerve, and peri‐neural saline, clonidine or a combination of clonidine and the &agr;2A‐adrenceptor‐preferring antagonist, BRL44408, were administered before wound closure and, in some animals, also 24 and 48 h later. The single clonidine injection reduced hypersensitivity for only 5 h, whereas repeated injection for three days reduced hypersensitivity for 28 days. Peri‐neural clonidine reduced the increase in tissue content of the proinflammatory cytokines IL‐1&bgr; and particularly TNF&agr; in sciatic nerve, DRG and spinal cord while increasing concentrations of the anti‐inflammatory cytokine TGF‐&bgr;1. Clonidines effects on behavior and TNF&agr; content were blocked by BRL44408. We conclude that peri‐neural administration of clonidine at the site and time of injury reduces the degree of hypersensitivity in part by altering the balance of pro‐ and anti‐inflammatory cytokines through activation of &agr;2A‐adrenoceptors. These results support testing of whether clonidine, as an adjuvant in continuous peripheral nerve blocks in settings of known major nerve injury, such as limb amputation, might prevent the development of chronic pain.

Exogenous and endogenous adenosine enhance the spinal antiallodynic effects of morphine in a rat model of neuropathic pain.

Adenosine analogs produce antinociception in normal animals and reduce allodynia and hyperalgesia following inflammation and nerve injury following spinal injection, yet none have been tested for clinical safety. While adenosine itself is in clinical trials for spinal administration, there is little data on the spinal effects of adenosine in animal models. In this study, we determined that the spinal administration of adenosine produced a dose-dependent reduction in tactile allodynia in rats following spinal nerve ligation without producing motor blockade. Although the maximal effect of adenosine was less than 50% reversal of allodynia, its duration of action was >24 h after a single spinal injection. In contrast, injection of a synthetic adenosine analog which produced an anti-allodynic action to a similar degree of effect resulted in a pronounced motor blockade. Spinal opioid action has been suggested to result in part from spinal adenosine release. We hypothesized that the reduced efficacy of spinal morphine in nerve injury-induced allodynia and hyperalgesia might reflect a disruption in this spinal opioid-adenosine mechanism. Spinal morphine itself produced a minimal reduction in allodynia in rats following spinal nerve ligation and this was enhanced in an additive manner by spinal adenosine. The maximal effect of this combination resulted in less than 60% reversal of allodynia. In contrast, spinal injection of adenosine deaminase or reuptake inhibitors greatly enhanced the effect of spinal morphine, resulting in over 80% reversal of allodynia. These results support the clinical testing of spinal adenosine alone and with morphine in the treatment of neuropathic pain, and further testing of the proposed opioid-adenosine link in normal and hyperesthetic conditions.

The short-lasting analgesia and long-term antihyperalgesic effect of intrathecal clonidine in patients undergoing colonic surgery.

In this study, we investigated the antihyperalgesic effect of clonidine after surgery. Sixty patients undergoing right colic resection were studied. Patients were randomized to receive prior to general anesthesia a 2-mL intrathecal (IT) injection of 300 &mgr;g of clonidine or saline, or 10 mg of bupivacaine. General anesthesia was achieved using a target concentration propofol infusion and monitored using bispectral index. Postoperative analgesia was provided by morphine IV given through a patient-controlled analgesia device. Postoperative analgesia was assessed by morphine requirements and visual analog scale pain scores at rest, cough, and movement during the first 72 h. Mechanical hyperalgesia was measured by von Frey filaments. Patients were questioned regarding residual pain at 2 wk,1, 6, and 12 mo. The patient-controlled analgesia morphine requirements were significantly smaller in the IT clonidine group (31.5 ± 12 versus 91 ± 25.5 and 43 ± 15 mg, respectively, in groups clonidine, saline, and bupivacaine: P < 0.05 at 72 postoperative hours). The area of hyperalgesia at 72 h was 3 ± 5 cm2 in the clonidine group versus 90 ± 30 and 35 ± 20 cm2 in the saline and bupivacaine groups (P < 0.05). At 6 mo, fewer patients in the clonidine group experienced residual pain than in the saline group (0 of 20 versus 6 of 20, P < 0.05). We conclude that both intraoperative spinal clonidine and bupivacaine improve immediate postoperative analgesia. IT clonidine was, however, more potent than IT bupivacaine to reduce postoperative secondary hyperalgesia.

Intrathecal ropivacaine and clonidine for ambulatory knee arthroscopy: a dose-response study.

BackgroundThe aim of this study was to evaluate the association of a small dose of intrathecal ropivacaine with small doses of intrathecal clonidine for ambulatory surgery. MethodsOne hundred twenty patients, classified as American Society of Anesthesiologists physical status I and scheduled for knee arthroscopy, were studied. Patients were randomly assigned to receive 4 ml of one of the following double-blinded isobaric intrathecal solutions: 8 mg of ropivacaine (group 1; n =30); 8 mg ropivacaine plus 15 &mgr;g clonidine (group 2; n =30); 8 mg ropivacaine plus 45 &mgr;g clonidine (group 3; n =30); and 8 mg ropivacaine plus 75 &mgr;g clonidine (group 4; n =30). The level and duration of sensory anesthesia were recorded, along with the intensity and duration of motor block. Patient and surgeon were interviewed to evaluate the quality of anesthesia. ResultsIntrathecal ropivacaine (8 mg alone) produced short sensory anesthesia and motor blockade (132 ± 38 min and 110 ± 35 min; mean ± SD). However, the quality of anesthesia was significantly lower than in any other group (P < 0.05). Ropivacaine (8 mg) plus 75 &mgr;g clonidine produced significantly longer sensory and motor anesthesia (195 ± 40 min and 164 ± 38 min;P < 0.05). However, this was associated with systemic effects, such as sedation and reduction of arterial blood pressure. Ropivacaine (8 mg) plus 15 &mgr;g clonidine did not prolong sensory or motor blockade, afforded high quality anesthesia, and was not associated with detectable systemic effects. ConclusionSmall-dose intrathecal clonidine (15 &mgr;g) plus 8 mg intrathecal ropivacaine produces adequate and short-lasting anesthesia for knee arthroscopy.