Ellen Jørum

EFNS guidelines on neuropathic pain assessment.

In September 2001, a Task Force was set up under the auspices of the European Federation of Neurological Societies with the aim of evaluating the existing evidence about the methods of assessing neuropathic pain and its treatments. This review led to the development of guidelines to be used in the management of patients with neuropathic pain. In the clinical setting a neurological examination that includes an accurate sensory examination is often sufficient to reach a diagnosis. Nerve conduction studies and somatosensory‐evoked potentials, which do not assess small fibre function, may demonstrate and localize a peripheral or central nervous lesion. A quantitative assessment of the nociceptive pathways is provided by quantitative sensory testing and laser‐evoked potentials. To evaluate treatment efficacy in a patient and in controlled trials, the simplest psychometric scales and quality of life measures are probably the best methods. A laboratory measure of pain that by‐passes the subjective report, and thus cognitive influences, is a hopeful aim for the future.

Relief of post-herpetic neuralgia with the N-methyl-D-aspartic acid receptor antagonist ketamine: a double-blind, cross-over comparison with morphine and placebo.

&NA; Pain and sensory thresholds were examined before and after intravenous administration of ketamine (0.15 mg/kg), morphine (0.075 mg/kg) or saline in 8 patients with post‐herpetic neuralgia. A randomized, double‐blind, cross‐over study design was used. Post‐herpetic neuralgia was associated with impaired sensory function, as shown by reduced tactile and warm sensation in the affected compared with the contralateral non‐affected skin area. Neither ketamine nor morphine changed significantly the thresholds for warm, cold, heat pain or tactile sensation. However, ketamine normalized abnormal heat pain sensations in 4 patients, probably due to a central effect. Ketamine, but not morphine, produced significant relief of pain. Pain evoked by non‐noxious stimulation of the skin (allodynia) was significantly inhibited by ketamine as well as by morphine. Wind‐up‐like pain (i.e., pain evoked by repeatedly pricking the affected skin area) was significantly inhibited by ketamine, but significantly aggravated by morphine. Side effects were observed in all the 8 patients after injection of ketamine and in 6 patients after injection of morphine. The present results support the hypothesis that the Symbol (NMDA) receptors are involved in the control of post‐herpetic neuralgia including allodynia and wind‐up‐like pain. The NMDA receptors also may play a role in the modulation of thermal perception. Symbol. No caption available

Cold allodynia and hyperalgesia in neuropathic pain: the effect of N-methyl-D-aspartate (NMDA) receptor antagonist ketamine--a double-blind, cross-over comparison with alfentanil and placebo.

&NA; Cold allodynia and hyperalgesia are frequent clinical findings in patients with neuropathic pain. While there have been several clinical studies showing the involvement of central sensitization mechanisms and N‐methyl‐d‐aspartate (NMDA) receptor activation in mechanical allodynia/hyperalgesia and ongoing pain, the mechanisms of thermal allodynia and hyperalgesia have received less attention. The aim of the present study was to examine the effect of the NMDA‐receptor antagonist ketamine on thermal allodynia/hyperalgesia, ongoing pain and mechanical allodynia/hyperalgesia in patients with neuropathic pain (11 patients with post‐traumatic neuralgia and one patient with post‐herpetic neuralgia). All the patients were known to suffer from severe cold allodynia (cold pain detection threshold (CPDT): 23.8°C, median value). The &mgr;‐opioid agonist alfentanil was used as an active control. The study design was double‐blind and placebo‐controlled and the drugs were administered i.v. (bolus dose and infusion). CPDT in the asymptomatic contralateral area was found to be significantly decreased (cold allodynia) compared to CPDT in site‐ and age‐matched normal controls. Heat pain detection thresholds were found to be normal and no consistent heat hyperalgesia occurred. Alfentanil significantly reduced cold allodynia (by increasing CPDT) in symptomatic area (P=0.0076). Ketamine did not significantly increase the threshold. Significant and marked reductions of hyperalgesia to cold (visual analogue score at threshold value) were seen following both alfentanil (4.5 before, 1.4 after, median value) and ketamine (6.8 before, 0.4 after, median value). Alfentanil and ketamine also significantly reduced ongoing pain and mechanical hyperalgesia. It is concluded that NMDA‐receptor mediated central sensitization is involved in cold hyperalgesia, but since CPDT remained unaltered, it is likely that other mechanisms are present.

Central suppression of cold-induced C fibre pain by myelinated fibre input

&NA; Changes in thermal sensibility for warmth, cold, heat pain and cold pain during nerve compression block of impulse conduction in myelinated fibres were studied in 20 healthy subjects. When mainly unmyelinated fibres were conducting, after 30–36 min of nerve compression, the pain threshold, induced by cold stimulation, was shifted towards higher temperatures (from 19.1° C to 22.8°C, mean values). Furthermore, the sensation of cold pain became more unpleasant and had a hot burning rather than a cold quality. These results indicate that a change in central decoding of the afferent input has occurred, possibly due to lack of inhibition normally exerted by concomitant activation of myelinated fibres. Whereas dramatic changes in the sensation of cold pain were observed during the course of nerve compression, no alteration in heat pain threshold was seen. This implies that heat pain threshold in hairy skin is due to activation of C nociceptor fibres without any significant contribution from myelinated nociceptor fibres. Furthermore, no gating from heat‐sensitive myelinated fibre input was evident on heat pain threshold.

Abnormal Function of C-Fibers in Patients with Diabetic Neuropathy

The mechanisms underlying the development of painful and nonpainful neuropathy associated with diabetes mellitus are unclear. We have obtained microneurographic recordings from unmyelinated fibers in eight patients with diabetes mellitus, five with painful neuropathy, and three with neuropathy without pain. All eight patients had large-fiber neuropathy, and seven patients had pathological thermal thresholds in their feet, indicating the involvement of small-caliber nerve fibers. A total of 163 C-fibers were recorded at knee level from the common peroneal nerve in the patients (36–67 years old), and these were compared with 77 C-fibers from healthy controls (41–64 years old). The ratio of mechano-responsive to mechano-insensitive nociceptors was ∼2:1 in the healthy controls, whereas in the patients, it was 1:2. In patients, a fairly large percentage of characterized fibers (12.5% in nonpainful and 18.9% in painful neuropathy) resembled mechano-responsive nociceptors that had lost their mechanical and heat responsiveness. Such fibers were rarely encountered in age-matched controls (3.2%). Afferent fibers with spontaneous activity or mechanical sensitization were found in both patient groups. We conclude that small-fiber neuropathy in diabetes affects receptive properties of nociceptors that leads to an impairment of mechano-responsive nociceptors.

Local treatment with the N-methyl-D-aspartate receptor antagonist ketamine, inhibit development of secondary hyperalgesia in man by a peripheral action.

Due to the recent discovery of peripheral N-methyl-D-aspartate (NMDA) (and other glutamate) receptors in animal studies, the NMDA receptor antagonist, ketamine (0.83 mg/ml, 6 ml) or saline was injected s.c. preinjury in 10 healthy volunteers, to study the effect on burn-induced primary and secondary hyperalgesia. On the saline treated leg, all subjects developed primary hyperalgesia and secondary hyperalgesia. On the contralateral leg treated with ketamine, there was a significant reduction of primary hyperalgesia and an inhibition of development of secondary hyperalgesia. In an experimental day 2, lidocaine temporarily blocked the development of primary and secondary hyperalgesia. When saline was injected in the contralateral leg treated with ketamine 1 week previously (n = 6), no zone of secondary hyperalgesia was developed. In contrast, subjects (n = 3) treated with ketamine 2 weeks before, reported development of secondary hyperalgesia following saline, a preliminary indication of a long-lasting peripheral action of ketamine.

High spontaneous activity of C-nociceptors in painful polyneuropathy

Summary Ongoing pain in peripheral neuropathy is linked to spontaneous activity in mechanoinsensitive nociceptors. The molecular mechanism differentiating painful from nonpainful neuropathy is still unclear. ABSTRACT Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C‐nociceptors in painful and painless polyneuropathy patients to identify pain‐specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C‐fibres including 214 C‐nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C‐nociceptors. The mean percentage of C‐nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P = .02). The difference was mainly due to more spontaneously active mechanoinsensitive C‐nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P = .02). The percentage of sensitized mechanoinsensitive C‐nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C‐nociceptors (Kendall’s tau = .55, P = .004). Moreover, spontaneous activity of mechanoinsensitive C‐nociceptors correlated to less pronounced activity‐dependent slowing of conduction (Kendall’s tau = −.48, P = .009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C‐nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C‐nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.

Preinjury treatment with morphine or ketamine inhibits the development of experimentally induced secondary hyperalgesia in man.

&NA; We examine the effect of morphine or ketamine (N‐methyl‐D‐aspartate receptor antagonist; NMDA) treatment on secondary hyperalgesia. Drug treatment started preinjury and continued into the early postinjury period. Hyperalgesia was induced by a local 1° burn injury covering 12.5 cm2 on the medial side of the calf. In this double‐blind, cross‐over study, 12 healthy volunteers received, on 3 separate days and in randomized order: (1) placebo; (2) morphine, bolus 150 &mgr;g/kg+infusion 1 &mgr;g/kg per min and 0.5 &mgr;g/kg per min; and (3) ketamine, bolus 60 &mgr;g/kg+infusion 6 &mgr;g/kg per min and 3 &mgr;g/kg per min. Bolus+infusion started 30 min before injury and ended 50 min after it. The area of secondary hyperalgesia was quantitated using punctate (von Frey filaments) and brush stimuli (electric brush). On the day of placebo, all subjects developed an area of hyperalgesia to punctate and brush stimuli outside the thermal injury (secondary hyperalgesia). We show that ketamine or morphine treatment starting preinjury significantly reduces this development (P<0.01, both). In a previous study, we found that postinjury treatment alone with morphine did not affect secondary hyperalgesia, whereas ketamine did so significantly. The differential response to morphine administered pre‐ or postinjury may be relevant to the recently shown NMDA receptor mediated interaction of central hyperexcitability and morphine antinociception. The effect of ketamine supports the hypothesis of the role of NMDA receptor mediation in central hyperexcitability.

Analgesia or hyperalgesia following stress correlates with emotional behavior in rats

&NA; Analgesia following exposure to a variety of noxious and non‐noxious Stressors is well documented and is commonly referred to as stress‐induced analgesia. Hyperalgesia following stress has also been reported. The present study shows that a mild Stressor (15 min of vibration) produced increased tail‐flick latencies (TFL) in some rats, but decreased latencies in other rats. The results of the individual subjects were reproduced in a later session: the rats showing increased TFL on day 1, responded with increased TFL on day 2. Rats showing decreased TFL on day 1 responded with decreased TFL on day 2. Whichever reaction occurred, analgesia or hyperalgesia, this correlated with the animals behavior during the stress procedure. Analgesia was produced in quiet rats and hyperalgesia in hyperemotional ones. Various peripheral nerve stimulation procedures producing hyperemotional reactions also resulted in lowering of the pain threshold. The results of the present study show behavioral modulation of pain mechanisms.

Role of TRPM8 and TRPA1 for cold allodynia in patients with cold injury.

Abstract Local cold injury often induces hypersensitivity to cold and cold allodynia. Sensitisation of TRPM8 or TRPA1 could be the underlying mechanisms. This was evaluated by psychophysics and axon‐reflex‐flare induction following topical menthol and cinnamaldehyde application in cold injury patients and healthy subjects. The patients had no signs of neuropathy except cold allodynia. We applied 20% cinnamaldehyde and 40% menthol solutions in the cold‐allodynic area of the patients and in a corresponding area in healthy subjects and obtained sensory ratings during application. Thermotesting and Laser Doppler Imaging were performed before and after exposure to the compounds. Menthol did not induce axon‐reflex‐erythema in patients or in controls. After menthol cold pain threshold was decreased in healthy subjects; however, no further sensitisation was observed in the patients moreover in some patients an amelioration of their cold allodynia was observed. Cinnamaldehyde‐induced pain sensation did not differ between patients and controls. Heat pain thresholds following cinnamaldehyde were lowered to a similar extent in patients and controls (43–39.8 and 44–39 °C) and also the axon‐reflex‐flare responses were comparable. No evidence for sensitisation of responses to TRPM8 or TRPA1‐stimulation was found in patients with cold injury‐induced cold allodynia. The lack of TRPM8 induced axon‐reflex indicates that also de‐novo expression of TRPM8 on mechano‐insensitive C‐nociceptors does not underlie cold allodynia in these patients. We conclude from these data that the mechanisms for the induction of cold allodynia in the patients with cold injury are independent of TRPM8 or TRPA1 and differ therefore from neuropathic pain patients.