Marcel Chauvin

The role of ketamine in preventing fentanyl-induced hyperalgesia and subsequent acute morphine tolerance

Perioperative opioids increase postoperative pain and morphine requirement, suggesting acute opioid tolerance. Furthermore, opioids elicit N-methyl-d-aspartate (NMDA)-dependent pain hypersensitivity. We investigated postfentanyl morphine analgesic effects and the consequences of NMDA-receptor antagonist (ketamine) pretreatment. The rat nociceptive threshold was measured by the paw-pressure vocalization test. Four fentanyl boluses (every 15 min) elicited a dose-dependent (a) increase followed by an immediate decrease of the nociceptive threshold and (b) reduction of the analgesic effect of a subsequent morphine administration (5 mg/kg): −15.8%, −46.6%, −85.1% (4 × 20, 4 × 60, 4 × 100 &mgr;g/kg of fentanyl, respectively). Ketamine pretreatment (10 mg/kg) increased the fentanyl analgesic effect (4 × 60 &mgr;g/kg), suppressed the immediate hyperalgesic phase, and restored the full effect of a subsequent morphine injection. Fentanyl also elicited a delayed dose-dependent long-lasting decrease of the nociceptive threshold (days) that was prevented by a single ketamine pretreatment before fentanyl. However, a morphine administration at the end of the fentanyl effects restored the long-lasting hyperalgesia. Repeated ketamine administrations were required to obtain a complete preventive effect. Although ketamine had no analgesic effect per se at the dose used herein, our results indicate that sustained NMDA-receptor blocking could be a fruitful therapy for improving postoperative morphine effectiveness.

Effects of Gabapentin on the Different Components of Peripheral and Central Neuropathic Pain Syndromes: A Pilot Study

Anticonvulsants are widely used in the treatment of neuropathic pain, and are assumed to act preferentially on lancinating, shooting pain. In the present study, the effects of gabapentin, a novel anticonvulsant, were evaluated systematically on both spontaneous and evoked pain in 18 patients with peripheral nerve injuries or central lesions. Gabapentin was administered orally in gradually increasing doses up to a maximum of 2,400 mg/day. Evaluations of spontaneous ongoing and paroxysmal pain, allodynia and hyperalgesia were performed at the beginning of the study (‘baseline’) and 6 weeks after the steady-state dose had been reached. Quantitative sensory tests were used to measure detection and pain thresholds to mechanical and thermal stimuli and the responses to suprathreshold stimuli. Gabapentin induced a moderate and statistically significant relief of ongoing spontaneous pain and was particularly effective in reducing paroxysmal pain. A striking finding was the significant effect on brush-induced and cold allodynia. In contrast, no effects were observed on detection and pain thresholds to static mechanical and hot stimuli. Side effects were generally minor and did not interfere with everyday activities. The present study suggests that gabapentin has preferential antihyperalgesic and/or antiallodynic effects, and is equally effective in pain due to peripheral nerve injuries and central lesions.

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.

“SUNCT” Syndrome. A Case of Transformation from Trigeminal Neuralgia?

A patient with typical trigeminal neuralgia involving the first branch of the nerve developed short-lasting unilateral attacks in the same area which were associated with severe vasomotor phenomena consistent with the recently described SUNCT syndrome. This evolution suggests that SUNCT might correspond, at least in this case, to a “transformed” trigeminal neuralgia and emphasizes the close relationship between these unilateral facial pain syndromes.

Effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on spontaneous and evoked pain in post-herpetic neuralgia.

The analgesic effects of single and repeated applications of a eutectic mixture of local anaesthetics (EMLA) cream on both spontaneous and evoked pains were evaluated in 11 patients with post-herpetic neuralgia (PHN). Detection thresholds, pain thresholds and the responses to suprathreshold mechanical and thermal stimuli were quantitatively determined at baseline, 30 min after the first application and after a series of daily applications over six consecutive days (duration of application: 5 h/day). In the acute situation, EMLA produced an overall anaesthetic effect without significantly reducing spontaneous ongoing pain and mechanical allodynia. Repeated applications significantly reduced paroxysmal pain and both the dynamic and static subtypes of mechanical hyperalgesia. The effects on spontaneous ongoing pain were more variable. They were inversely correlated to the magnitude of the thermal deficit at baseline, and were significant only in patients with dynamic mechano-allodynia. Pathophysiological implications of these results are discussed.

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.

Nefopam strongly depresses the nociceptive flexion (RIII) reflex in humans

Nefopam hydrochloride has been commercialized as an analgesic drug in most Western European countries for 20 years. It has been shown to possess analgesic activity with a profile distinct from that of opioids or anti-inflammatory drugs. In order to define the mechanisms of action of this pharmacological agent, we studied, in a double-blind and cross-over fashion, its effects on the nociceptive flexion (R(III)) reflex and the corresponding pain sensation in ten healthy volunteers. The R(III), reflex elicited by electrical stimulation of the sural nerve was recorded from the biceps femoris. Two experiments were performed on each volunteer at an interval of 7 days. On each experimental day, four recruitment (intensity-response) curves of the R(III) reflex were constructed: before (control period) and then 30, 60 and 90 min after the intravenous injection of nefopam (20 mg) or a placebo. Nefopam induced a powerful depression of the nociceptive R(III) reflex. It increased the threshold of the reflex and decreased the slope of the recruitment curve. At the same time, it decreased the painful sensations (as measured with a visual analogue scale(VAS)) elicited by the maximum stimulus intensity. These data suggest that nefopam probably produces its analgesic action through central (spinal and/or supraspinal) mechanisms. However, complementary peripheral mechanisms cannot be excluded on the basis of the present study. In view of these results, it seems that new clinical studies will have to be undertaken to revisit this potent analgesic agent and try to limit its adverse effects (i.e. nausea, vomiting, sweating). Its fast onset of action could clearly be an advantage, notably in the treatment of post-operative pain.

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.