Timo Kauppila

NeuPSIG guidelines on neuropathic pain assessment

&NA; This is a revision of guidelines, originally published in 2004, for the assessment of patients with neuropathic pain. Neuropathic pain is defined as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system either at peripheral or central level. Screening questionnaires are suitable for identifying potential patients with neuropathic pain, but further validation of them is needed for epidemiological purposes. Clinical examination, including accurate sensory examination, is the basis of neuropathic pain diagnosis. For more accurate sensory profiling, quantitative sensory testing is recommended for selected cases in clinic, including the diagnosis of small fiber neuropathies and for research purposes. Measurement of trigeminal reflexes mediated by A‐beta fibers can be used to differentiate symptomatic trigeminal neuralgia from classical trigeminal neuralgia. Measurement of laser‐evoked potentials is useful for assessing function of the A‐delta fiber pathways in patients with neuropathic pain. Functional brain imaging is not currently useful for individual patients in clinical practice, but is an interesting research tool. Skin biopsy to measure the intraepidermal nerve fiber density should be performed in patients with clinical signs of small fiber dysfunction. The intensity of pain and treatment effect (both in clinic and trials) should be assessed with numerical rating scale or visual analog scale. For future neuropathic pain trials, pain relief scales, patient and clinician global impression of change, the proportion of responders (50% and 30% pain relief), validated neuropathic pain quality measures and assessment of sleep, mood, functional capacity and quality of life are recommended.

Assessment of Neuropathic Pain in Primary Care

Management of patients presenting with chronic pain is a common problem in primary care. Essentially, the classification of chronic pain falls into 3 broad categories: (1) pain owing to tissue disease or damage (nociceptive pain), (2) pain caused by somatosensory system disease or damage (neuropathic pain), and (3) pain without a known somatic background. Key challenges in developing a targeted holistic approach to treatment include appropriate diagnosis of the cause or causes of pain; identifying the type of pain and assessing the relative importance of its various components; and determining appropriate treatment. In clinical examination, sensory abnormalities are the crucial findings leading to a diagnosis of neuropathic pain, for which pharmacotherapy with antidepressants and anticonvulsants represents the cornerstone of medical treatment. Chronic neuropathic pain is underrecognized and undertreated, yet primary care physicians are uniquely placed on the frontlines of patient management, where they can play a pivotal role in treatment and prevention through diagnosis, therapy, follow-up, and referral. This review provides guidance in understanding and identifying the neuropathic contribution to pain presenting in primary care; assessing its severity through patient history, physical examination, and appropriate diagnostic tests; and establishing a rational treatment plan.

Behavioural measures of depression and anxiety in rats with spinal nerve ligation-induced neuropathy

The behaviour of rats with spinal nerve ligation-induced neuropathic pain was studied using tests developed to measure depression and anxiety. Adult male Sprague-Dawley rats were tested with the open field test, elevated plus maze, two compartment test and forced swimming test. Spontaneous motility was measured in a photocell observation box. Mechanical sensitivity was tested with von Frey hairs and cold sensitivity with the acetone drop test. The L5-6 spinal nerves were ligated or a sham operation was performed and the rats were followed for 2 weeks before the same set of tests were repeated. Most of the neuropathy operated rats had mechanical and cold allodynia. With post-injury there was a significant decrease in the activity in the open field test and motility box tests, when compared with the pre-injury results. In the elevated plus maze test there was a significant reduction in the motility, but there was no change in the time spent in the closed wings. In the two compartment test there were no significant differences between the pre- and post-injury results. There were no differences between the rats with spinal nerve ligation injury and the sham operated rats in any of the tests. The results were also comparable when rats that developed a high degree of neuropathy were compared with the rats with low degree of neuropathy and the sham operated group. In conclusion, spinal nerve ligation injury of the spinal nerves L5-6 induces mechanical and cold allodynia, but it does not seem to produce general suffering or measurable anxiety to the animals. Furthermore, tests for anxiety and depression were not able to predict which animals were vulnerable to express symptoms of neuropathic pain after nerve injury.

Induction of type IV collagen and other basement-membrane-associated proteins after spinal cord injury of the adult rat may participate in formation of the glial scar.

We investigated the spatial and temporal expression of basement-membrane-forming and neurite-outgrowth-supporting matrix proteins after a unilateral dorsal root injury combined with a collagen I/laminin-1 graft and a stab wound lesion to the dorsal horn of the adult rat spinal cord. Ten days after injury, the gamma1 laminin was induced in the reactive glia. At this early stage, the glial cells failed to express type IV collagen and the alpha1 laminin. One month after injury, reactive astrocytes in the dorsal horn of the lesioned side expressed gamma1 laminin, type IV collagen, and the alpha1 laminin whereas astrocytes of the normal spinal cord or the uninjured contralateral dorsal horn were negative. Both astrocytes and neurons of the ipsilateral ventral horn were induced to express laminin-1 and gamma1 laminin. Astrocytes of the ipsilateral ventral horn also expressed type IV collagen. Simultaneously with the changes in expression of the extracellular matrix proteins, the expression pattern of basic fibroblast growth factor (FGF-2) was markedly altered after spinal cord injury. In normal and contralateral spinal cord, FGF-2 was expressed in nerve fibers, but its expression changed from neuronal into glial in the ipsilateral spinal cord within 1 month after injury. Four months after injury, expression of both type IV collagen and the alpha1 laminin had declined, but the astrocytes at the injury site continued expressing the gamma1 laminin. Cultured astrocytes were negative for type IV collagen, but several cytokines, including IL-1beta and TGFbeta1, induced expression of type IV collagen in the astrocytes. These factors also increased deposition of type IV collagen matrix in the glial cultures. These results indicate that type IV collagen and the alpha1 laminin are induced in reactive astrocytes after spinal cord injury in vivo. Induction of type IV collagen in astrocytes in vitro by cytokines indicates that blood-borne or local factors at the injury site may induce the spinal cord glial expression of type IV collagen in vivo. Simultaneous expression of laminin-1 and alpha1 laminin with type IV collagen is known to lead to production of basement membranes. This may hamper the neurite-outgrowth-promoting potential of the gamma1 laminin by initiating formation of the glial scar.

Influence of spinalization on spinal withdrawal reflex responses varies depending on the submodality of the test stimulus and the experimental pathophysiological condition in the rat

The influence of midthoracic spinalization on thermally and mechanically induced spinal withdrawal reflex responses was studied in the rat. There were three experimental groups of rats: healthy controls, rats with a spinal nerve ligation-induced unilateral neuropathy, and rats with a carrageenan-induced inflammation of one hindpaw. Tail flick response was induced by radiant heat. Hindlimb withdrawal was induced by radiant heat, ice water, and innocuous or noxious mechanical stimulation of the paw. Prior to spinalization, spinal nerve ligated and carrageenan-treated animals had a marked unilateral allodynia and hyperalgesia. Spinalization tended to induce a facilitation of noxious heat-evoked reflexes. This spinalization-induced facilitation was stronger on tail than hindlimb withdrawal. Spinalization-induced skin temperature change did not explain the facilitation of noxious heat-evoked reflexes. In contrast, spinal withdrawal responses induced by noxious cold or mechanical stimulation were significantly suppressed following spinalization. The spinalization-induced facilitatory effects as well as inhibitory ones on spinal reflexes were enhanced in inflamed/neuropathic animals. The results indicate that the tonic descending control of spinal nocifensive responses varies depending on the submodality of the test stimulus, the segmental level of the reflex (tail vs. hindlimb), and on the pathophysiological condition.

Effect of systemic medetomidine, an alpha2 adrenoceptor agonist, on experimental pain in humans

The effect of systemic (intravenous) medetomidine, an alpha-2 adrenoceptor agonist, on pain thresholds was studied in healthy human subjects (n = 6). Medetomidine produced a dose-dependent (cumulative doses: 25 and 50 micrograms) sedative effect evaluated by visual analog scale. Also, a dose-dependent decrease of blood pressure but not of heart rate was seen after administration of medetomidine. Pain threshold to electric stimulation of the tooth pulp and cutaneous heat pain threshold were uninfluenced by medetomidine. An index of cutaneous thermal sensitivity to innocuous stimuli, the width of the thermoneutral zone, also was uninfluenced by medetomidine. Medetomidine produced a significant attenuation of the affective-motivational component (unpleasantness) of tourniquet-induced ischemic pain, whereas the sensory-discriminative component (pain magnitude estimate) of the ischemic pain was not attenuated. The results suggest that systemic medetomidine alone at subanesthetic but sedative and hypotensive doses does not significantly influence the intensity and thresholds of experimental pain, whereas the affective-motivational component of pain can be attenuated.

Weight bearing of the limb as a confounding factor in assessment of mechanical allodynia in the rat

&NA; Effect of weight bearing of the hindlimbs on the assessment of mechanically‐induced hindlimb withdrawal threshold was determined in intact rats and in rats with various pathophysiological conditions causing allodynia or hyperalgesia. Hindlimb withdrawal was elicited by applying a series of calibrated monofilaments to the plantar or the dorsal surface of the paw. During testing the rat was either in a restraint tube with hindlimbs hanging semi‐extended without weight bearing or it was standing on a metal grid (bearing its own weight). In intact rats, the withdrawal thresholds were significantly lower when the stimulus site was the dorsal hairy skin rather than the plantar glabrous skin. Also, thresholds were significantly lower when the hindlimbs were not bearing weight. Following carrageenan‐induced unilateral inflammation of the plantar paw or a tibial nerve cut there was a marked threshold decrease to test stimuli applied to plantar or dorsal paw, respectively, ipsilateral to the pathological condition in standing rats. However, when the hindlimbs were not weight bearing the unilateral threshold decrease was markedly attenuated (carrageenan‐treated rats) or completely abolished (tibial cut). In contrast, in rats with a unilateral spinal nerve ligation the threshold decrease ipsilateral to the nerve lesion was highly significant independent of the weight bearing of the hindlimbs. The results indicate that weight bearing of hindlimbs is an important confounding factor in the assessment of tactile allodynia in rats.

The effect of medetomidine, an α2-adrenoceptor agonist, in various pain tests

Abstract Medetomidine, a new α 2 -adrenoceptor agonist produced dose-depndent (30–100 μg/kg i.p.) analgesia in the formalin test in rats, and this effect was reversed by atipamezole (1 mg/kg), a new α 2 -adrenoceptor antagonist. However, medetomidine at the dose of 100 μg/kg did not influence tail flick latencies or latencies of the biting response to mechanical pinch stimuli. Moreover, medetomidine produced sedation and a decrease in locomotor activity. In comparison, the non-sedative monoaminergic agent, cocaine (25 mg/kg), produced highly significant analgesic effects in the formalin and mechanical pain tests. The cocaine effect in the formalin test was not reversed by atipamezole (1 mg/kg). It is concluded that the analgesic effect of medetomidine in the formalin test is due to supraspinal mechanisms related to sedation and is mediated by α 2 -adrenoceptors. The α 2 -adrenoceptors are not involved in cocaine-induced anagesia.

Inhibition of intestinal motility and reversal of postlaparotomy ileus by selective α2-adrenergic drugs in the rat

BACKGROUND The effects of selective alpha-agonist medetomidine and alpha 2-antagonist atipamezole on gastrointestinal motility were studied. METHODS The passage of intragastrically administered Evans blue in the small bowel of unanesthetized rats was followed, and the stomachs were weighted after killing the rats. RESULTS Subcutaneous medetomidine, 0.01-0.1 mg/kg, was found to delay small intestinal transit but not gastric emptying, with a maximal effect seen at 0.03 mg/kg. Atipamezole fully reversed the effect of 0.1 mg/kg of medetomidine with a dose of 2.5 mg/kg. Atipamezole alone did not affect small intestinal transit. Subcutaneous morphine, 6 mg/kg, delayed gastric emptying and small intestinal transit, whereas intraperitoneal morphine only delayed gastric emptying. Subcutaneous atipamezole, 0.06 mg/kg, was partially able to reverse the delayed intestinal transit but did not inhibit morphine-induced gastric retention. Subcutaneous atipamezole, 0.06 mg/kg, reversed laparotomy-induced ileus completely. CONCLUSIONS Atipamezole may provide a useful treatment for postlaparotomy ileus.

Dissociation of the α2-adrenergic antinociception from sedation following microinjection of medetomidine into the locus coeruleus in rats

&NA; It is well established that &agr;‐adrenoceptor agonists have sedative and antinociceptive properties. In the current behavioral study we tried to find out if the &agr;‐adrenergic sedative and antinociceptive effects can be dissociated. We tested the hypothesis that &agr; adrenergic sedation is mediated by the locus coeruleus (LC) and antinociception by spinal &agr;‐adrenoceptors. Also, we addressed the possibility that intracerebral injection of an &agr;‐agonist might produce its antinociceptive effect by an action directly at the spinal cord. Medetomidine, an &agr;‐adrenergic agonist, or atipamezole, an &agr;‐adrenergic antagonist, were microinjected bilaterally into the LC through chronic cannulae in unanesthetized Han‐Wistar rats. The effect on locomotor activity (/vigilancc). tail‐flick and hot‐plate response, and on formalin‐induced pain behavior was determined. Medetomidine microinjected into the LC (1–10 &mgr;g/cannula) produced dose‐dependently hypolocomotion (/sedation), increase of response latencies in the hot‐plate and the tail‐flick tests, and a decrease in the formalin‐induced pain behavior. Hypolocomotion (/sedation) was obtained at a lower medetomidine dose (1 &mgr;g/cannula) than antinociception (3–10 &mgr;g/cannula). The lowest medetomidine dose used (1 &mgr;g/cannula), which induced significant hypolocomotion (/sedation), produced either no antinociception (hot‐plate and tail‐flick tests) or even a slight hyperalgesia (formalin test). The hypolocomotion (/sedation) but not antinociception (tail‐flick test) induced by systemic administration of medetomidine (100 &mgr;g/kg s.c.) could be reversed by atipamezole (10 &mgr;g/cannula) microinjected into the LC. Only a high systemic dose of atipamezole (1 mg/kg s.c.) reversed the antinociceptive effects of medetomidine. Microinjection of medetomidine into the LC (3 &mgr;g/cannula) produced antinociception (tail‐flick test) also in spinal rats. which effect was completely reversed by atipamezole (l mg/kg s.c.). Following administration of medetomidine at the dose of 1 &mgr;g/cannula into the central or cortical nucleus of the amygdala (control sites) there was no significant effect on locomotor activity, hot‐plate response, or formalin‐induced pain. The results indicate that &agr;‐adrenergic sedative and pain‐modulating effects can be dissociated following microinjection of medetomidine into the LC. The antinociceptive effect of the supraspinally microinjected medetomidine in Han‐Wistar rats could be explained by direct activation of the spinal &agr;‐adrenoceptors, whereas the sedation/hypolocomotion could he explained by an action on the &agr;‐adrenoceptors located in the LC, or its immediate vicinity.