D. Fletcher

A patient-based national survey on postoperative pain management in France reveals significant achievements and persistent challenges

&NA; We carried out a national survey on postoperative pain (POP) management in a representative sample (public/private, teaching/non‐teaching, size) of 76 surgical centers in France. Based on medical records and questionnaires, we evaluated adult patients 24 h after surgery, concerning information: pre and postoperative pain, evaluation, treatment and side effects. A local consultant provided information about POP management. Data were recorded for 1900 adult patients, 69.3% of whom remembered information on POP. Information was mainly delivered orally (90.3%) and rarely noted on the patient’s chart (18.2%). Written evaluations of POP were frequent on the ward (93.7%) with appropriate intervals (4.1 (4.0) h), but not frequently prescribed (32.7%). Pain evaluations were based on visual analog scale (21.1%), numerical scale (41.2%), verbal scale (13.8%) or non‐numerical tool (24%). Pain was rarely a criterion for recovery room discharge (19.8%). Reported POP was mild at rest (2.7 (1.3)), moderate during movement (4.9 (1.9)) and intense at its maximal level (6.4 (2.0)). Incidence of side effects was similar according to patient (26.4%) or medical chart (25.1%) including mostly nausea and vomiting (83.3%). Analgesia was frequently initiated during anesthesia (63.6%). Patient‐controlled analgesia (21.4%) was used less frequently than subcutaneous morphine (35.1%) whose prescription frequently did not follow guidelines. Non‐opioid analgesics used included paracetamol (90.3%), ketoprofen (48.5%) and nefopam (21.4%). Epidural (1.5%) and peripheral (4.7%) nerve blocks were under used. Evaluation (63.4%) or treatment (74.1%) protocols were not available for all patients. This national, prospective, patient‐based, survey reveals both progress and persistent challenges in POP management.

Opioid-induced hyperalgesia in patients after surgery: a systematic review and a meta-analysis

BACKGROUNDnOpioids can increase sensitivity to noxious stimuli and cause opioid-induced hyperalgesia. We performed a systematic review to evaluate the clinical consequences of intra-operative doses of opioid.nnnMETHODSnWe identified randomized controlled trials which compared intra-operative opioid to lower doses or placebo in adult patients undergoing surgery from MEDLINE, EMBASE, LILAC, Cochrane, and hand searches of trial registries. We pooled data of postoperative pain intensity, morphine consumption, incidence of opioid-related side-effects, primary and secondary hyperalgesia. For dichotomous outcomes relative risks [95% confidence intervals (CIs)] and for continuous outcomes mean differences (MDs) or standardized mean difference (SMD; 95% CI) were calculated.nnnRESULTSnTwenty-seven studies involving 1494 patients were included in the analysis. Patients treated with high intra-operative doses of opioid reported higher postoperative pain intensity than the reference groups (MD: 9.4 cm; 95% CI: 4.4, 14.5) at 1 h, (MD: 7.1 cm; 95% CI: 2.8, 11.3) at 4 h, and (MD: 3 cm; 95% CI: 0.4, 5.6) at 24 h on a 100 cm visual analogue scale. They also showed higher postoperative morphine use after 24 h (SMD: 0.7; 95% CI: 0.37, 1.02). There was no difference in the incidences of nausea, vomiting, and drowsiness. These results were mainly associated with the use of remifentanil. The impact of other opioids is less clear because of limited data.nnnDISCUSSIONnThis review suggests that high intra-operative doses of remifentanil are associated with small but significant increases in acute pain after surgery.

Long term effects of oral sustained release morphine on neuropsychological performance in patients with chronic non-cancer pain.

&NA; Morphine is increasingly used in patients with chronic non‐cancer pain, but a major concern associated with chronic use relates to possible cognitive side‐effects. The aim of this long‐term prospective study was to evaluate the cognitive impact of oral sustained release morphine in patients with non‐cancer pain. A battery of neuropsychological tests to explore attention, psychomotor speed and memory was administered. The effects of morphine on pain, quality of life, mood, subjective memory impairment and side‐effects were also investigated. Evaluations were performed at baseline in patients free from opioids and then after 3, 6 and 12 months. Twenty‐eight patients were included: 18 received oral sustained morphine (range 40–140 mg/day), ten patients stopped morphine prematurely because of side‐effects or insufficient pain relief and were followed as a control group. There was no impairment of any neuropsychological variable over time in the morphine treated patients in comparison with the control group. Two measures of information processing speed – the Stroop interference score and the digit symbol test were improved at 6 and 12 months and there were significant correlations with the pain relief and improvement of mood. Self‐reported memory impairment improved notably in responders to morphine. Morphine induced persisting effects on pain, and to a lesser extent on quality of life and mood. The visual analog scale score for side‐effects increased at 12 months and essentially consisted of gastrointestinal disorders. This study demonstrates that 12 months treatment with oral morphine does not disrupt cognitive functioning in patients with chronic non‐cancer pain and instead results in moderate improvement of some aspects of cognitive functioning, as a consequence of the pain relief and concomitant improvement of well‐being and mood.

Interaction of a combination of morphine and ketamine on the nociceptive flexion reflex in human volunteers.

&NA; Experimental studies in animals have suggested that a combination of morphine and N‐methyl‐d‐aspartate (NMDA) receptor antagonists may have additive or synergistic analgesic effects. To further study the nature of the interaction between these two classes of analgesic agents, we analyzed the effects of morphine, ketamine and their combination on electrophysiological recordings of the nociceptive flexion RIII reflex in 12 healthy volunteers. Morphine (0.1 mg/kg), ketamine (0.1 mg/kg followed by 4 &mgr;g/kg/min) or their combination were administered intravenously according to a double‐blind, placebo controlled and cross‐over design. The RIII reflex was recorded from the biceps femoris and elicited by electrical stimulation of the sural nerve. The effects of the drugs were tested on: (1) the stimulus–response curves of the reflex up to the tolerance threshold (frequency of stimulation: 0.1 Hz); (2) the progressive increase of the reflex and painful sensations (i.e. wind‐up phenomenon) induced by a series of 15 electrical stimuli at a frequency of 1 Hz (intensity: 20% above threshold). The stimulus–response curve of the nociceptive RIII reflex was significantly reduced after injection of a combination of ketamine and morphine, but was not modified when placebo or each of the active drugs was administered alone. The wind‐up of the RIII reflex and painful sensation was not significantly altered after the injection of placebo, ketamine, morphine or their combination. In conclusion, the present electrophysiological results in humans demonstrate a synergistic interaction between morphine and ketamine, which tends to confirm the interest of using this type of combination in the clinical context. The differential effects observed on the recruitment curve and wind‐up indicate, however, that the mechanisms of the interaction between opiates and NMDA receptor antagonists are not univocal but depend on the modality of activation of the nociceptive afferents.

Risk factors predictive of chronic postsurgical neuropathic pain: the value of the iliac crest bone harvest model.

Summary Acute neuropathic characteristics and secondary hyperalgesia are independent, additive factors predictive of chronic postsurgical pain after iliac crest bone harvest. ABSTRACT Nerve lesions and secondary hyperalgesia may both be present after surgery, and their relative contributions to chronic postsurgical neuropathic pain (CPSNP) remain unclear. This prospective study explored the roles of these factors in the development of CPSNP after iliac crest bone harvest. CPSNP was defined as pain in the area of hypoesthesia, with a positive Douleur neuropathique 4 questionnaire (DN4) score 3 months after iliac crest bone harvest. The location, intensity, and neuropathic characteristics of pain were evaluated in 82 patients who were followed for 6 months. Neuropathic characteristics were assessed by clinical examination and DN4 questionnaire. The area of secondary hyperalgesia was evaluated 48 h and 1 month after surgery. The area of mechanical hypoesthesia, detection, and mechanical pain threshold were evaluated at 48 h and at 1 and 3 months. Nineteen patients (23%) had CPSNP at 3 months. The patients who developed CPSNP had a larger area of secondary hyperalgesia at 48 h (88 cm2 vs 33 cm2; P = .001), higher pain intensity (numerical rating scale 6.7 vs 4.7; P = .02), and higher neuropathic characteristics score on the DN4 questionnaire (4.3 vs 2.3; P = .001). However, neither the area nor the severity of hypoesthesia differed significantly between patients with and without CPSNP. Two independent, additive predictors of CPSNP were identified: area of secondary hyperalgesia (odds ratio 1.02; P = .004) and DN4 score (odds ratio 1.94; P = .001). These findings suggest that both nerve lesions and central sensitization are involved in CPSNP development and could be seen as early warning signs.

The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: A randomized, double-blind, controlled study

&NA; Perioperative minocycline administration for 8 days after lumbar discectomy does not improve persistent pain. &NA; Minocycline strongly inhibits microglial activation, which contributes to central sensitization, a major mechanism underlying chronic pain development. We hypothesized that the perioperative administration of minocycline might decrease persistent pain after lumbar discectomy. We randomly assigned 100 patients undergoing scheduled lumbar discectomy to placebo and minocycline groups. The minocycline group received 100 mg minocycline orally, twice daily, beginning the evening before surgery and continuing for 8 days. The primary outcome was the change in lower limb pain intensity at rest between baseline and 3 months. Secondary outcomes were pain intensity on movement, the incidence of persistent pain and chronic neuropathic pain, back pain intensity at rest and on movement, and changes in Neuropathic Pain Symptom Inventory, Brief Pain Inventory, and Roland‐Morris scores at 3 months. An intention‐to‐treat analysis was performed for patients assessed from the day before surgery to 3 months. The decrease in lower limb pain intensity was similar in the placebo and minocycline groups, both at rest −1.7 ± 1.6 vs −2.3 ± 2.4 and on movement −2.5 ± 2.1 vs −3.4 ± 2.9. The incidence and intensity of neuropathic pain and functional scores did not differ between the minocycline and placebo groups. Exploratory analysis suggested that minocycline might be effective in a subgroup of patients with predominantly deep spontaneous pain at baseline. Perioperative minocycline administration for 8 days does not improve persistent pain after lumbar discectomy.

Small fibre impairment predicts neuropathic pain in Guillain–Barré syndrome

&NA; The mechanisms of neuropathic pain (NP) in Guillain Barré syndrome (GBS) are currently unknown. It has recently been shown that acute neuropathy of GBS not only affects large myelinated fibres but also small nociceptive fibres. In this prospective longitudinal 18 months study, we investigated the role of small fibre impairment in NP in GBS (n = 30). Small fibres were assessed by quantifying cold and warm detection and pain thresholds and responses to suprathreshold painful thermal and mechanical stimuli. Nerve conduction velocities and mechanical detection thresholds assessed large myelinated fibres. Detection thresholds particularly at the lower limbs were significantly impaired in patients with GBS compared to 15 healthy controls. GBS patients with NP (n = 13) had more severe impairment of cold detection thresholds (p = 0.04), heat pain thresholds (p = 0.03) and responses to suprathreshold heat stimuli (p = 0.017) in the foot compared with those without pain or with non‐neuropathic pain (n = 17). Large fibre dysfunction and motor disability were similar between groups. Small fibre sensory impairment at the acute stage was correlated with the intensity of burning pain (Rho: −0.72; p = 0.01 for cold detection; Rho: 0.72; p = 0.02 for heat pain) and predicted residual NP (odds 4.1 p = 0.04 for heat pain). These findings emphasize the importance of nociceptive fibre impairment in NP in GBS at both acute and chronic stages and suggest similarities between the mechanisms of NP in GBS and those of small fibre painful sensory polyneuropathies.

The analgesic efficiency of combined pregabalin and ketamine for total hip arthroplasty: a randomised, double-blind, controlled study.

Ketamine and pregabalin each provide postoperative analgesia, although the combination has yet to be evaluated. One hundred and forty‐two patients undergoing total hip arthroplasty were randomly assigned to receive ketamine alone, pregabalin alone, ketamine and pregabalin combined, or placebo. Pain scores at rest and on movement, morphine consumption, side‐effects, pressure pain thresholds and secondary hyperalgesia were evaluated. Mean (SD) total 48‐h morphine use was reduced in patients given ketamine alone (52 (22) mg) and pregabalin alone (44 (20) mg) compared with placebo (77 (36) mg) p < 0.001. Morphine use was further reduced in patients given both ketamine and pregabalin (38 (19) mg) with an interaction between ketamine and pregabalin (ANOVA factorial; p = 0.028). Secondary hyperalgesia was reduced by ketamine. There were no differences between groups in pain scores after surgery, pressure pain thresholds or side‐effects. The combination of pregabalin and ketamine has a small, beneficial clinical effect.

Effect of combining tramadol and morphine in adult surgical patients: a systematic review and meta-analysis of randomized trials

The role for tramadol in multimodal postsurgical analgesic strategies remains unclear. We undertook a systematic review to evaluate the utility of combining tramadol with morphine after surgery. We searched the MEDLINE, EMBASE, LILAC, Cochrane, and Clinical Trial Register databases for randomized, controlled studies comparing tramadol with placebo or active control in patients undergoing surgery. Fourteen studies (713 patients) were included. There was a limited but significant postoperative morphine-sparing effect, with a weighted mean difference (WMD) of -6.9 (95% confidence interval -11.3 to -2.5) mg. This effect was not associated with a decrease in morphine-related adverse effects. No difference in the incidence of nausea, vomiting, sedation, or shivering was observed. There was no decrease in pain intensity at 24 h; the WMD was -0.9 (-7.2; 5.2) on a 100 mm visual analogue scale at 24 h. We found no significant clinical benefit from the combination of i.v. tramadol and morphine after surgery.

II. Dexamethasone and peripheral nerve blocks: on the nerve or intravenous?

In a past issue of the British Journal of Anaesthesia, Desmet and colleagues report that i.v. dexamethasone is equivalent to perineural dexamethasone in prolonging the analgesic duration of a single-shot interscalene block with ropivacaine. In their study, 150 patients presenting for arthroscopic shoulder surgery with an interscalene brachial plexus block (BPB) were randomized into three groups: ropivacaine 0.5%; ropivacaine 0.5% and dexamethasone 10 mg; and ropivacaine 0.5% with i.v. dexamethasone 10 mg. The primary outcome was the duration of analgesia, defined as the time between performance of the block and the first analgesic request. The median time of a sensory block was equivalent for perineural and i.v. dexamethasone: 1405 min (inter-quartile range 1015–1710) and 1275 min (inter-quartile range 1095–2035) ropivacaine and perineural dexamethasone and ropivacaine and i.v. dexamethasone, respectively. There was a significant difference between the ropivacaine group: 757 min (interquartile range 635–910) and the dexamethasone groups (P1⁄40.0001). The authors conclude that i.v. dexamethasone is equivalent to perineural dexamethasone in prolonging the analgesic duration of a single-shot interscalene block with ropivacaine. Legitimate criticisms have been made on the design of this study such as the sample size calculation, a non-inferiority design based on a large difference in duration of analgesia for the equivalence limit (i.e. 360 min), or the reality of the intention-to-treat analysis. 3 Although we cannot definitely say based on a single study that the duration of analgesia is equivalent with perineural or i.v. dexamethasone added to single-shot interscalene block, this study’s results should not be ignored and future studies with a larger sample of patients may conclusively answer the question. It has been shown that continuous peripheral nerve blocks, regardless of catheter location, provided superior postoperative analgesia and fewer opioid-related side-effects when compared with opioid analgesia. However, painful procedures previously requiring inpatient hospital admission for pain control, such as shoulder surgery, are now commonly performed as ambulatory procedures facilitated by nerve block analgesia. Inevitably, the effects of single injection dissipate after several hours unmasking the moderate-to-severe pain of the surgical insult. A majority of surgical patients consistently rank postoperative pain as their highest concern highlighting the necessity for prolonged postoperative analgesia. Since efforts to prolong single-shot peripheral nerve block analgesia by increasing local anaesthetic dose are limited by their narrow therapeutic window, strategies include the co-administration of adjuvants such as epinephrine, a2 agonists (i.e. clonidine and dexmedetomidine), – 7 opioid, or more recently the corticosteroid dexamethasone. All published prospective studies until the recent report by Desmet and colleagues have described a benefit of the addition of perineural dexamethasone to prolong the duration of analgesia. – 17 These data concern only single-shot BPBs with a similar number of studies using longor intermediate-acting local anaesthetic. A recent large retrospective study suggests a similar advantage for upper and lower limb nerve block. A meta-analysis has confirmed this impression by analysing nine trials testing the impact of dexamethasone on BPB. These trials included 801 patients with 393 patients receiving dexamethasone (4–10 mg) and dexamethasone prolonged the analgesic duration for long-acting local anaesthetic from 730 to 1306 min [mean difference 576 min, 95% confidence interval (CI) 522–631] and for intermediate from 168 to 343 min (mean 175, 95% CI 73–277). Motor block was prolonged from 664 to 1102 min (mean 438, 95% CI 89–787). The authors of this meta-analysis conclude that perineural administration of dexamethasone with local anaesthetic prolongs BPB effects with no observed adverse events. They also insist on the necessity to investigate the effects of systemic administration of dexamethasone on peripheral nerve block analgesia. In fact, the recent study by Desmet and colleagues is the only one to have compared systemic with local administration of dexamethasone and found no clinical significant difference. BJA Editorial II