Article

Tactile allodynia in patients with lumbar radicular pain (sciatica)

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Abstract

Unlabelled: We report a novel symptom in many patients with low back pain (LBP) that sheds new light on the underlying pain mechanism. By means of quantitative sensory testing, we compared patients with radicular LBP (sciatica), axial LBP (LBP without radiation into the leg), and healthy controls, searching for cutaneous allodynia in response to weak tactile and cooling stimuli on the leg and low back. Most patients with radicular pain (~60%) reported static and dynamic tactile allodynia, as well as cooling allodynia, on the leg, often extending into the foot. Some also reported allodynia on the low back. In axial LBP, allodynia was almost exclusively on the back. The degree of dynamic tactile allodynia correlated with the degree of background pain. The presence of allodynia suggests that the peripheral nerve generators of background leg and back pain have also induced central sensitization. The distal (foot) location of the allodynia in patients who have it indicates that the nociceptive drive that maintains the central sensitization arises paraspinally (ectopically) in injured ventral ramus afferents; this is not an instance of somatic referred pain. The presence of central sensitization also provides the first cogent account of shooting pain in sciatica as a wave of activity sweeping vectorially across the width of the sensitized dorsal horn. Finally, the results endorse leg allodynia as a pain biomarker in animal research on LBP, which is commonly used but has not been previously validated. In addition to informing the underlying mechanism of LBP, bedside mapping of allodynia might have practical implications for prognosis and treatment. Social media question: How can you tell whether pain radiating into the leg in a patient with sciatica is neuropathic, ie, due to nerve injury?

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... Although authors claimed to address HACS in six studies [45,52,53,63,66,71], they did not describe assessment methods that could estimate HACS in the method section of their study. ...
... The CSI scores resulted in a prevalence of 71.1% (n = 128) [46]. The presence of tactile allodynia resulted in a prevalence of 60.8% (n = 74) in patients with CLBP+, a prevalence of 13.3% (n = 15) in patients with CLBP only [52] and PPT combined with TS resulted in a prevalence of 18.3% (n = 104)) [64]. Based on these 3 studies (n = 321), the mean prevalence of HACS in patients with CLBP was 48.9%. ...
... HACS can present itself in many symptoms and/or manifestations such as altered CPM, decreased pain thresholds, increased temporal summation, and the presence of widespread pain) but can, until today, not directly be demonstrated in humans [24]. In three studies, patients were appointed to groups with and without HACS based on CSI or QST assessment outcomes [46,52,64]. In all other studies, methods were used to assess HACS, but no conclusion about the presence or absence of HACS could be drawn. ...
Article
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Central sensitisation is assumed to be one of the underlying mechanisms for chronic low back pain. Because central sensitisation is not directly assessable in humans, the term 'human assumed central sensitisation' (HACS) is suggested. The objectives were to investigate what definitions for HACS have been used, to evaluate the methods to assess HACS, to assess the validity of those methods, and to estimate the prevalence of HACS. Database search resulted in 34 included studies. Forty different definition references were used to define HACS. This review uncovered twenty quantitative methods to assess HACS, including four questionnaires and sixteen quantitative sensory testing measures. The prevalence of HACS in patients with chronic low back pain was estimated in three studies. The current systematic review highlights that multiple definitions, assessment methods, and prevalence estimates are stated in the literature regarding HACS in patients with chronic low back pain. Most of the assessment methods of HACS are not validated but have been tested for reliability and repeatability. Given the lack of a gold standard to assess HACS, an initial grading system is proposed to standardize clinical and research assessments of HACS in patients with a chronic low back.
... A larger territory of allodynia in the sciatic nerve distribution may reflect a greater degree of central sensitization. 129 Symptoms of central sensitization in sciatica include tactile and thermal allodynia 129 as well as pressure sensitivity of muscle (somatic) tissue. 130 Over half (60%) of those with radicular sciatica have allodynia of the lower extremity, whereas those with localized LBP only rarely have this symptom. ...
... 130 Over half (60%) of those with radicular sciatica have allodynia of the lower extremity, whereas those with localized LBP only rarely have this symptom. 129 Those with widespread tenderness are less likely to have discogenic sciatica. One study found that patients with sciatica and more than 8 tender points were less likely to have nerve root compression in the lumbar spine (OR 0.15) 131 and more likely to have normal lumbar MRI (OR 1.39). ...
... This includes, for example, nociceptors in the annulus fibrosus 321 or dorsal horn of the spinal cord. 129 Elevated venous pressure may also stimulate nociceptors in the lumbar vertebrae. 322 The presence Figure 170: Image A: Normal flow of venous blood in the lumbar spine is towards the inferior vena cava, which flows cranially to the heart. ...
Chapter
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• Combinations of tests help rule the spine and nerve root involvement in or out • Deficits are more pronounced in those with radicular sciatica compared to extraspinal or myofascial sciatica • Red flag signs may prompt urgent or emergent referral
... Central sensitization may be responsible for allodynia throughout the sciatic nerve distribution in those with sciatica. 12,27 Over half of those with radicular sciatica have hypersensitivity to low-intensity stimulation of the skin. 12 It is thought that this is because low level mechanoreceptive input is amplified in the dorsal horn and perceived as painful. ...
... 12,27 Over half of those with radicular sciatica have hypersensitivity to low-intensity stimulation of the skin. 12 It is thought that this is because low level mechanoreceptive input is amplified in the dorsal horn and perceived as painful. 12 The sensation of shooting pain from the back to the leg or foot in radicular sciatica is thought to result from a sweeping wave of neural activity in the sensitized dorsal horn of the spinal cord. ...
... 12 It is thought that this is because low level mechanoreceptive input is amplified in the dorsal horn and perceived as painful. 12 The sensation of shooting pain from the back to the leg or foot in radicular sciatica is thought to result from a sweeping wave of neural activity in the sensitized dorsal horn of the spinal cord. 12 Sensory neurons from the lower back synapse more laterally in the dorsal horn compared to the leg neurons which synapse more medially. ...
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• Common features of sciatica include mechanosensitivity, inflammation, and swelling along the sciatic nerve pathway • These occur in sciatic pain originating from within or outside the spine • Central or peripheral sensitization may explain these common features
... Amongst these models, the most widely used method for inducing chronic LBP in rodents is the IVD puncture model as it yields a progressive and reproducible degeneration, similar to the changes observed in humans (Daly et al., 2016). Although few studies have described the associated pain behavioral phenotypes (Olmarker, 2008;Kim et al., 2011;Henry et al., 2012;Li et al., 2014;Lai et al., 2015Lai et al., , 2016, a significant limitation of many previous models is that they mimic lumbar radicular pain more closely than chronic mechanical (discogenic) LBP in humans (Devor and Tal, 2009;Defrin et al., 2014). This is in part due to the removal and/or leakage of nucleus pulposus (NP) from the IVDs in these rodent models and their possible exposure to the adjacent sensory nerve roots, resulting in lumbar radicular pain (Takahashi et al., 2008). ...
... These models are also useful for screening novel compounds from drug discovery to identify those with potential to be highly efficacious and well-tolerated novel analgesics and/or adjuvants (Muralidharan et al., 2013). Previously reported rodent models of chronic LBP where there is prominent development of mechanical allodynia in the hindpaws (Hu and Xing, 1998;Tachihara et al., 2007;Gu et al., 2008;Amaya et al., 2009;Henry et al., 2012;Lai et al., 2015) akin to lumbar radicular pain in humans (Defrin et al., 2014), have been critically questioned (Devor and Tal, 2009). This is because typical patients with chronic mechanical LBP do not report prominent neuropathic pain symptoms in the lower extremities (Devor and Tal, 2009;Defrin et al., 2014). ...
... Previously reported rodent models of chronic LBP where there is prominent development of mechanical allodynia in the hindpaws (Hu and Xing, 1998;Tachihara et al., 2007;Gu et al., 2008;Amaya et al., 2009;Henry et al., 2012;Lai et al., 2015) akin to lumbar radicular pain in humans (Defrin et al., 2014), have been critically questioned (Devor and Tal, 2009). This is because typical patients with chronic mechanical LBP do not report prominent neuropathic pain symptoms in the lower extremities (Devor and Tal, 2009;Defrin et al., 2014). ...
Article
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Chronic low back pain (LBP), the leading cause of disability globally, is notoriously difficult to treat. Most rodent models of LBP mimic lumbar radicular pain rather than mechanical LBP. Here, we describe establishment of a new rat model of mechanical LBP that is devoid of a neuropathic component. Groups of adult male Sprague Dawley rats were anesthetized and their lumbar L4/L5 and L5/L6 intervertebral disks (IVDs) were punctured (0.5 mm outer diameter, 2mm-deep) 5 (LPB-5X), or 10 (LBP-10X) times per disk. Sham-rats underwent similar surgery, but without disk puncture. Baseline noxious pressure hyperalgesia of lumbar axial deep tissues, mechanical allodynia in the hindpaws and gait were assessed prior to surgery and once-weekly until study completion on day 49. The model was also characterized using pharmacologic and histologic methods. Good animal health was maintained for ≥ 49 days post-surgery. For LBP- but not sham-rats, there was temporal development of noxious pressure hyperalgesia in lumbar axial deep tissues at days 14–49 post-surgery. Importantly, there were no between-group differences in von Frey paw withdrawal thresholds or gait parameters until study completion. On day 49, significant histologic changes were observed in the L4/L5 and L5/L6 IVDs for LBP-10X rats, but not sham-rats. In LBP-10X rats, single bolus doses of morphine produced dose-dependent relief of primary and secondary mechanical hyperalgesia in lumbar axial deep tissues at L4/L5 and L1, respectively. In conclusion, our new rat model has considerable potential for providing novel insight on the pathobiology of mechanical LBP and for analgesic efficacy assessment of novel compounds.
... For most individuals, it is relatively easy to distinguish between innocuous and noxious stimuli. However, in a subset of individuals afflicted with chronic pain, there is a disturbance of normal somatosensory function, such that a normally innocuous stimulus can evoke pain, for example, the emergence of tactile allodynia in patients with sciatica (1). This can have a debilitating impact on both the individual and society (2,3). ...
... In the current study, the co-infusion of sub-perceptual NS resulted in increased HS-pain (i.e., hyperalgesia). In HS and other experimental models as well as chronic pain conditions, tactile and thermal stimuli can produce allodynia (pain to a normally nonpainful stimulus) and hyperalgesia (increased pain from a painful stimulus) (1,4,6), but paradoxically, these modulatory stimuli-both painful and nonpainful-can also reduce pain with slow gentle brushing of the skin shown to reduce cutaneous heat pain (28). Conditioned pain modulation is a well-recognized phenomenon in which a painful stimulus can be inhibited by a second painful stimulus applied to a different body site (i.e., pain inhibits pain) (29)(30)(31). ...
Article
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We have previously shown that during muscle pain induced by infusion of hypertonic saline (HS), concurrent application of vibration and gentle brushing to overlying and adjacent skin regions increases the overall pain. In the current study, we focused on muscle-muscle interactions and tested whether HS-induced muscle pain can be modulated by innocuous/sub-perceptual stimulation of adjacent, contralateral, and remote muscles. Psychophysical observations were made in 23 healthy participants. HS (5%) was infused into a forearm muscle (flexor carpi ulnaris) to produce a stable baseline pain. In separate experiments, in each of the three test locations (n = 10 per site)-ipsilateral hand (abductor digiti minimi), contralateral forearm (flexor carpi ulnaris), and contralateral leg (tibialis anterior)-50 µl of 0.9% normal saline (NS) was infused (in triplicate) before, during, and upon cessation of HS-induced muscle pain in the forearm. In the absence of background pain, the infusion of NS was imperceptible to all participants. In the presence of HS-induced pain in the forearm, the concurrent infusion of NS into the ipsilateral hand, contralateral forearm, and contralateral leg increased the overall pain by 16, 12, and 15%, respectively. These effects were significant, reproducible, and time-locked to NS infusions. Further, the NS-evoked increase in pain was almost always ascribed to the forearm where HS was infused with no discernible percept attributed to the sites of NS infusion. Based on these observations, we conclude that intramuscular infusion of HS results in muscle hyperalgesia to sub-perceptual stimulation of muscle afferents in a somatotopically unrestricted manner, indicating the involvement of a central (likely supra-spinal) mechanism.
... Likewise, the DRG is implicated as a driver of pain in herpes zoster and postherpetic neuralgia, trigeminal neuralgia (TN), phantom limb pain, and complex regional pain syndrome. 5,8,14,[37][38][39][40]49 Ablative procedures aimed at the DRG and trigeminal ganglion are used frequently in the treatment of chronic pain, notably TN, chronic headaches, and occipital neuralgia. More recently, electrical counterstimulation directed at the DRG has been introduced as a therapeutic modality in a variety of chronic pain conditions. ...
... Conditions in which the DRG is implicated as a pain driver include postherpetic neuralgia, a pain state caused by viral infection of a single ganglion, TN where fifth nerve root compression triggers hyperexcitability within the trigeminal ganglion, phantom pain, complex regional pain syndrome, and radicular low back pain. 5,8,14,15,33,37 The principle also applies to pain generated at focal sites of nerve injury such as nerve-end neuromas and nerve entrapment sites. 12 The 5% lidocaine patch is an example of such focal targeting. ...
Article
Ectopic impulse discharge (ectopia) generated in the soma of afferent neurons in dorsal root ganglia (DRGs) following nerve injury is thought to be a major contributor to neuropathic pain. The DRG is thus a prime interventional target. The process of electrogenesis (impulse generation) in the DRG is far more sensitive to systemically administered Na channel blockers than the process of impulse propagation along sensory axons. It should therefore be possible to selectively suppress DRG ectopia with local application of membrane stabilizing agents without blocking normal impulse traffic. Results from in vivo electrophysiological recordings in rats showed that epidural application of lidocaine to the DRG surface within the intervertebral foramen at 0.02% or 0.2% substantially suppresses electrogenesis in the DRG with only a modest blocking effect on impulse propagation through the foramen. Topically applied opiates and GABA, in contrast, blocked neither ongoing discharge nor spike through-conduction. This suggests that sustained intraforaminal delivery of dilute lidocaine, and by extension other membrane stabilizing agents, is a potential new strategy for the control of chronic painful conditions in which ectopia in sensory ganglia is implicated as a key pain driver. Such conditions include postherpetic neuralgia, trigeminal neuralgia, phantom limb pain, CRPS and radicular low back pain.
... Neuropathic pain (NP) is defined as "pain arising as a direct consequence of a lesion or disease affecting the somatosensory system" 6 . The identification and classification of NLBP þ/À leg pain is difficult due to its heterogeneity and remains one of the most challenging chronic pain disorders to treat 3,[7][8][9] . At present, patients are still generally classified on a trial and error basis influenced by which clinician they have attended, and there is a suggestion that clinicians fail to identify significant NLBP þ/À leg pain 3,10 . ...
... However, there was a lack of agreement between studies as to which specific descriptors are most accurate in distinguishing between the two LBP groups. 8 M. HERAUGHTY AND C. RIDEHALGH ...
Article
Objective: Descriptors provided by patients with neuropathic low back pain (NLBP) with or without spinally referred leg pain are frequently used by clinicians to help to identify the predominant pain mechanisms. Indeed, many neuropathic screening tools are primarily based on subjective descriptors to determine the presence of neuropathic pain. There is a need to systematically review and analyse the existing evidence to determine the validity of such descriptors in this cohort. Methods: Ten databases were systematically searched. The review adhered to PRISMA and CRD guidelines and included a risk of bias assessment using QUADAS-2. Studies were included if they contained symptom descriptors from a group of NLBP patients +/-leg pain. Studies had to include a reference test to identity neuropathic pain from other pain mechanisms. Results: Eight studies of 3,099 NLBP patients were included. Allodynia and numbness were found to discriminate between NLBP and nociceptive LBP in 4 studies. Autonomic dysfunction, (changes in the colour or appearance of the skin), was also found to discriminate between the groups in 2 studies. Dysesthesia identified NLBP in 5/7 respectively. Results from studies were equivocal regarding pain described as hot/burning cold and paroxysmal pain in people with NLBP. Conclusion: Subjectively reported allodynia and numbness would suggest a neuropathic pain mechanism in LBP. Dysesthesia would raise the suspicion of NLBP. More research is needed to determine if descriptors suggesting autonomic dysfunction can identify NLBP. There is poor consensus on whether other descriptors can identify NLBP.
... The presence of central sensitization, however, can be inferred from tactile allodynia in the affected body part in patients with radicular LBP and TN. 11,13,30 If pain moves or expands, it is probably not referred pain. Spread of pain also occurs in chronic regional pain syndrome, although the rate is usually measured in weeks and months, not seconds or minutes. ...
Article
Patients with radicular low back pain (radicular LBP, sciatica) frequently describe their pain as "shooting" or "radiating." The dictionary meaning of these words implies rapid movement, and indeed, many sufferers report feeling pain moving rapidly from the lower back or buttock into the leg. But, others do not. Moreover, the sensation of movement is paradoxical; it is neither predicted nor accounted for by current ideas about the pathophysiology of radicular LBP. We have used a structured questionnaire to evaluate the sensory qualities associated with "shooting" and "radiating" in 155 patients, 98 with radicular LBP and 57 with trigeminal neuralgia, a second chronic pain condition in which shooting/radiating are experienced. Results indicated a spectrum of different sensations in different people. Although many sciatica patients reported rapid downward movement of their pain, even more reported downward expansion of the area of pain, some reported upward movement, and for some, there was no spatial dynamic at all. The velocity of movement or expansion was also variable. By cross-referencing sensations experienced in the sciatica and trigeminal neuralgia cohorts with known signal processing modes in the somatosensory system, we propose testable hypotheses concerning the pathophysiology of the various vectorial sensations reported, their direction and velocity, and the structures in which they are generated. Systematic evaluation of qualitative features of "shooting" and "radiating" pain at the time of diagnosis can shed light on the pain mechanism in the individual patient and perhaps contribute to a better therapeutic outcomes.
... We have previously shown that the DRG inflammation model causes a naproxen-sensitive decrease in a more complex behavior (rearing) [42]. Interestingly, a recent study showed that many human patients with radicular (but not axial) low back pain also exhibited hypersensitivity to von Frey and cold stimuli in the leg and foot [15]. ...
Article
High frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all the isoforms in adult DRG, NaV1.6 is the main carrier of TTX-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRGs showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons, and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch clamp recordings of TTX-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current; effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6.
... For example, during straight-leg lifting, mechanical force is applied to the ganglion by tensioning the sciatic nerve. In patients with radicular low back pain, this gives rise to ectopic firing and shooting leg pain [18,68,84]. The DRG is located proximally in the PNS, in the intervertebral foramen. ...
Chapter
Pain in herpes zoster and postherpetic neuralgia is classically ascribed to irritable, inflammation-sensitized nociceptors in the cutaneous rash and to spinal cord deafferentation. After considering weaknesses in the evidence base underlying this view an alternative explanation is offered, based on hyperexcitability at ectopic pacemaker sites in affected primary sensory neurons, and central sensitization induced and maintained by the ectopic activity.
... Pathological stimuli or injury to peripheral nervous system can result in painful neuropathies that commonly share clinical features such as light touch-evoked pain (allodynia), burning sensation, exaggerated responses to noxious stimuli (hyperalgesia), and either spontaneous or evoked unpleasant abnormal sensations (dysesthesia) 16 . These symptoms are widely considered due to the hyperexcitability of primary sensory neurons [17][18][19][20] and the ectopic activation of the voltage-gated ion channels including the sensory neuron specific voltage gated sodium channel 1.8 (NaV1.8) 21 . ...
Article
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Neuronal cells express considerable plasticity responding to environmental cues, in part, through subcellular mRNA regulation. Here we report on the extensive changes in distribution of mRNAs in the cell body and axon compartments of peripheral sensory neurons and the 3′ untranslated region (3′UTR) landscapes after unilateral sciatic nerve entrapment (SNE) injury in rats. Neuronal cells dissociated from SNE-injured and contralateral L4 and L5 dorsal root ganglia were cultured in a compartmentalized system. Axonal and cell body RNA samples were separately subjected to high throughput RNA sequencing (RNA-Seq). The injured axons exhibited enrichment of mRNAs related to protein synthesis and nerve regeneration. Lengthening of 3′UTRs was more prevalent in the injured axons, including the newly discovered alternative cleavage and polyadenylation of NaV1.8 mRNA. Alternative polyadenylation was largely independent from the relative abundance of axonal mRNAs; but they were highly clustered in functional p
... Animal studies have identified the DRG as a second major locus of ectopic spontaneous and evoked electrogenesis in peripheral neuropathy, and there is indirect evidence of this also in humans. 13,41,45,47,54,79,80,89 Indeed, the DRG may be a more important source of ectopic discharge than neuroma endbulbs. 50 Because DRG infection is the root cause of HZ/PHN, involvement of the DRG as an impulse generator in this condition seems likely a priori. ...
Article
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Introduction Pain in herpes zoster (HZ) and postherpetic neuralgia (PHN) is traditionally explained in terms of 2 processes: irritable nociceptors in the rash-inflamed skin and, later, deafferentation due to destruction of sensory neurons in one virally infected dorsal root ganglion. Objectives and methods Consideration of the evidence supporting this explanation in light of contemporary understanding of the pain system finds it wanting. An alternative hypothesis is proposed as a replacement. Results This model, the ectopic pacemaker hypothesis of HZ and PHN, proposes that pain in both conditions is driven by hyperexcitable ectopic pacemaker sites at various locations in primary sensory neurons affected by the causative varicella zoster virus infection. This peripheral input is exacerbated by central sensitization induced and maintained by the ectopic activity. Conclusions The shift in perspective regarding the pain mechanism in HZ/PHN has specific implications for clinical management.
... So far, to reveal the underlying mechanism of radicular low back pain, a number of preclinical models have been developed that attempt to mimic the above known causes of low back pain [1,2]. Amongst those, chronic compression of the dorsal root ganglion (CCD) model in rodents displayed dramatic pain hypersensitivity such as mechanical hypersensitivity (hyperalgesia and allodynia) and thermal hyperalgesia that mimic the pain symptom observed in low back pain patients [1][2][3][4][5][6]. Although epidural steroid injection and surgical intervention have been used both clinically and experimentally in many cases, radicular low back pain remains a common chronic pain condition that is sometimes refractory to current treatment modalities [7,8]. ...
Article
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Evidence has accumulated that reactive oxygen species and inflammation play crucial roles in the development of chronic pain, including radicular low back pain. Nonsteroid anti-inflammatory drugs (NSAIDs), for example, salicylic acid, aspirin, provided analgesic effects in various types of pain. However, long-term use of these drugs causes unwanted side effects, which limits their implication. Stable nitronyl (NIT) nitroxide radicals have been extensively studied as a unique and interesting class of new antioxidants for protection against oxidative damage. The present study synthesized a novel NIT nitroxide radical with salicylic acid framework (SANR) to provide synergistic effect of both antioxidation and antiinflammation. We demonstrated for the first time that both acute and repeated SANR treatment exerted dramatic analgesic effect in radicular low back pain mimicked by chronic compression of dorsal root ganglion in rats. This analgesic potency was more potent than that produced by classical NSAIDs aspirin and traditional nitroxide radical Tempol alone. Furthermore, SANR-induced behavioral analgesia is found to be mediated, at least in partial, by a reduction of ectopic spontaneous discharges in injured DRG neurons. Therefore, the synthesized NIT nitroxide radical coupling with salicylic acid framework may represent a novel potential therapeutic candidate for treatment of chronic pain, including radicular low back pain.
... It will be of considerable interest to examine VGLL3 and its immune target genes in the context of chronic pain. Interestingly, according to a research survey developed on behalf of the American Migraine Prevalence Prevention Advisory Group, among patients suffering from migraine-associated pain, cutaneous allodynia is more common in women, those with a higher body mass index, and those who are disabled or depressed [285], and tactile allodynia is a common symptom in patients coping with sciatica [286]. ...
Article
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Chronic pain occurs with greater frequency in women, with a parallel sexually dimorphic trend reported in sufferers of many autoimmune diseases. There is a need to continue examining neuro-immune-endocrine crosstalk in the context of sexual dimorphisms in chronic pain. Several phenomena in particular need to be further explored. In patients, autoantibodies to neural antigens have been associated with sensory pathway hyper-excitability, and the role of self-antigens released by damaged nerves remains to be defined. In addition, specific immune cells release pro-nociceptive cytokines that directly influence neural firing, while T lymphocytes activated by specific antigens secrete factors that either support nerve repair or exacerbate the damage. Modulating specific immune cell populations could therefore be a means to promote nerve recovery, with sex-specific outcomes. Understanding biological sex differences that maintain, or fail to maintain, neuroimmune homeostasis may inform the selection of sex-specific treatment regimens, improving chronic pain management by rebalancing neuroimmune feedback. Given the significance of interactions between nerves and immune cells in the generation and maintenance of neuropathic pain, this review focuses on sex differences and possible links with persistent autoimmune activity using sciatica as an example.
... Two included studies assessed central sensitization. 27,38 No studies assessed peripheral sensitization. Scerbo et al, in a systematic review of studies using the Central Sensitization Inventory (CSI), reported high-quality evidence supporting psychometric properties and face validity, suggesting the instrument is useful in measuring central sensitization severity. ...
Article
Objective: The purpose of this systematic review is to evaluate and summarize current evidence for diagnosis of common conditions causing low back pain and to propose standardized terminology use. Methods: A systematic review of the scientific literature was conducted from inception through December 2018. Electronic databases searched included PubMed, MEDLINE, CINAHL, Cochrane, and Index to Chiropractic Literature. Methodological quality was assessed with the Scottish Intercollegiate Guidelines Network checklists. Results: Of the 3995 articles screened, 36 (8 systematic reviews and 28 individual studies) met final eligibility criteria. Diagnostic criteria for identifying likely discogenic, sacroiliac joint, and zygapophyseal (facet) joint pain are supported by clinical studies using injection-confirmed tissue provocation or anesthetic procedures. Diagnostic criteria for myofascial pain, sensitization (central and peripheral), and radicular pain are supported by expert consensus-level evidence. Criteria for radiculopathy and neurogenic claudication are supported by studies using combined expert-level consensus and imaging findings. Conclusion: The absence of high-quality, objective, gold-standard diagnostic methods limits the accuracy of current evidence-based criteria and results in few high-quality studies with a low risk of bias in patient selection and reference standard diagnosis. These limitations suggest practitioners should use evidence-based criteria to inform working diagnoses rather than definitive diagnoses for low back pain. To avoid the unnecessary complexity and confusion created by multiple overlapping and nonspecific terms, adopting International Association for the Study of Pain terminology and definitions is recommended.
... Defrin et al suggested that tactile allodynia might be present in 60% of patients with chronic LBP associated with radicular pain. 56 In this kind of patient the use of MT could be excessively painful, and any MT that triggers pain should be avoided. 57 ST-and therefore a possible placebo effectcould represent a valid alternative to MT in the multidisciplinary approach to back pain, promoting pain relief without increasing the possibility of AE occurrence. ...
Article
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Objective To assess the effects and reliability of sham procedures in manual therapy (MT) trials in the treatment of back pain (BP) in order to provide methodological guidance for clinical trial development. Design Systematic review and meta-analysis. Methods and analysis Different databases were screened up to 20 August 2020. Randomised controlled trials involving adults affected by BP (cervical and lumbar), acute or chronic, were included. Hand contact sham treatment (ST) was compared with different MT (physiotherapy, chiropractic, osteopathy, massage, kinesiology and reflexology) and to no treatment. Primary outcomes were BP improvement, success of blinding and adverse effect (AE). Secondary outcomes were number of drop-outs. Dichotomous outcomes were analysed using risk ratio (RR), continuous using mean difference (MD), 95% CIs. The minimal clinically important difference was 30 mm changes in pain score. Results 24 trials were included involving 2019 participants. Very low evidence quality suggests clinically insignificant pain improvement in favour of MT compared with ST (MD 3.86, 95% CI 3.29 to 4.43) and no differences between ST and no treatment (MD -5.84, 95% CI −20.46 to 8.78). ST reliability shows a high percentage of correct detection by participants (ranged from 46.7% to 83.5%), spinal manipulation being the most recognised technique. Low quality of evidence suggests that AE and drop-out rates were similar between ST and MT (RR AE=0.84, 95% CI 0.55 to 1.28, RR drop-outs=0.98, 95% CI 0.77 to 1.25). A similar drop-out rate was reported for no treatment (RR=0.82, 95% 0.43 to 1.55). Conclusions MT does not seem to have clinically relevant effect compared with ST. Similar effects were found with no treatment. The heterogeneousness of sham MT studies and the very low quality of evidence render uncertain these review findings. Future trials should develop reliable kinds of ST, similar to active treatment, to ensure participant blinding and to guarantee a proper sample size for the reliable detection of clinically meaningful treatment effects. PROSPERO registration number CRD42020198301.
Article
Background context Low back pain is one of the most common musculoskeletal disorders. While the pathology of intervertebral disc (IVD) degeneration has been modeled using various biological methods, these models are inadequate for simulating similar pathological states in humans. Purpose This study investigated whether monosodium iodoacetate (MIA) injection into the IVD of rats could generate a reliable model of IVD degeneration. Study design/settings In vivo animal study. Methods MIA was injected into two disc spaces (L4-5 and L5-6) of Sprague–Dawley rats. Their behaviors were examined by measuring weight load shifts from hind to forefoot, rearing, and von Frey tests. We examined the inhibition of pain behavior through intraperitoneal morphine injection and measured cyclooxygenase-2 (COX-2) and transcription factor nuclear factor-kappa B (NF-κB) levels in the IVD and dorsal root ganglion (DRG) by Western blot. Bone alterations were assessed by microfocus computed tomography (micro-CT), and IVD/cartilage changes were evaluated by hematoxylin and eosin and safranin-O staining and inducible nitric oxide synthase (iNOS) immunohistochemistry. The other authors declare no conflicts of interest. This project funded by the Memorial Fund and the National Research Foundation of Korea (NRF). Results We observed increased weight load shifts to the forefoot and decreased rearing. Morphine-injected rats showed reduced pain. NF-κB and COX-2 expression increased in the IVD and left/right DRG. Micro-CT analyses suggested progressive bone deformation. Histological examination showed decreased IVD width and nucleus pulposus area. Cartilaginous changes indicated epiphyseal growth plate loss. Finally, iNOS expression was increased in the subchondral endplate. Conclusions These results suggest that low back pain (LBP) models can be developed by MIA injection into the IVDs of rats and that an animal model is useful for exploring degenerative alterations in the affected discs. Therefore, MIA injection may be a useful model for the study of changes in the IVD to elucidate the mechanisms underlying clinical symptoms, such as LBP, in patients with IVD degeneration. Clinical significance This model in which MIA was injected into the disc better represented the human histological and behavioral characteristics than the existing puncture model.
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Among all chronic pain problems and spinal pain conditions, low back pain (LBP) is the most common clinical and public health problem (Deyo et al. Spine (Phila Pa 1976) 31(23):2724–7, 2006). It is the leading cause of activity limitation and work absence throughout much of the world. There is a lack of consensus evidence for the indication and efficacy for many spine surgeries and interventions. Evidence of randomized controlled trials showed inconsistent results, depending on the setting of the study (Andersson et al. Spine (Phila Pa 1976) 31(14):1637–8, 2006; Freeman et al. Spine (Phila Pa 1976) 30(21):2369–77, 2005; Buchbinder et al. N Engl J Med 361(6):557–68, 2009; Wardlaw et al. Lancet 373(9668):1016–24, 2009; Manchikanti et al. Pain Physician 18(1):79–92, 2015; Friedly et al. N Engl J Med 371(1):11–21, 2014; Juch et al. (JAMA 318(1):68–81, 2017; Dreyfuss et al. Spine (Phila Pa 1976) 25(10):1270–7, 2000). There are multiple factors contributing to this reality. Diagnosis of spinal pathology that underlies the clinical LBP often is difficult. Correlation between anatomic pathology and clinical symptoms is weak. In this article, we will review the anatomic base of spinal pain, focusing on low back pain, and discuss some of the common potential “pain generators” and their overlapping symptomology. We will highlight the prevalence and characteristics of neuropathic pain in chronic LBP, emphasizing the change of somatosensory function and central neural processes in individuals with chronic LBP. We will discuss some of the comorbid psychological dysfunction in chronic LBP patients and its various penetrance in individual patients, as it relates to treatment outcomes. We propose a chronic LBP-focused registry to collect relevant information across the biopsychosocial domains of pain and outcome measurements, to guide individualized treatment.
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Residual lower limb pain after low back surgery (post-surgical sciatica) and complex regional pain syndrome involving a lower limb (CRPS) are separate conditions, but may share some mechanisms (e.g., tissue inflammation, neuro-immune disturbances and central neuro-plasticity). As adrenergically-evoked pain contributes, in part, to CRPS, whether an adrenergic mechanism also contributes to post-surgical sciatica was investigated in this study. Immunohistochemistry was used to identify α1-adrenoceptors (α1-AR) on nerve fibres and other targets in the affected and contralateral skin of 25 patients with post-surgical sciatica, and α1-AR expression was investigated in relation to pain and pinprick hyperalgesia after intradermal injection of the α1-AR agonist phenylephrine. In addition, quantitative sensory testing was performed on all four limbs and on each side of the forehead. α1-AR expression was greater in keratinocytes (but not blood vessels or nerve fibres) in the symptomatic than contralateral leg, and dermal nerve fibre density was reduced in both legs. However, distal adrenergic involvement in pain in post-surgical sciatica seems unlikely, as neither heightened α1-AR expression in keratinocytes nor reduced dermal nerve fibre density were associated with pain or hyperalgesia to intradermal phenylephrine injection. Sensitivity to pressure-pain, pinprick and cold-pain was greater in the ipsilateral than contralateral forehead of the entire cohort, but sensory disturbances were most pronounced in patients with additional CRPS-like features. Together, these findings suggest that bilateral distal neuropathy and central neuro-plastic changes are involved not only in the pathophysiology of CRPS but also in post-surgical sciatica. This may have treatment implications for patients with post-surgical sciatica.
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Low back pain (LBP) is a highly prevalent and disabling condition whose initiating factors are poorly understood. It is known that psychological and physical stress is associated with LBP but the causal relationship, mechanisms and mediators have not been elucidated, and a preclinical model enabling the investigation of causality and thereby critically contributing to clinical translation does not exist.In the present study, we first established and characterized a myofascial LBP model in mice based on NGF injection into the low back muscles. Secondly, we investigated the effect of two different stress paradigms on this mouse LBP model by applying the chronic unpredictable stress (CUS) and vertical chronic restraint stress (vCRS) paradigms, to mimic psychological and psychophysical stress, respectively. In these studies, we combined longitudinal behavioral tests with gene and protein expression analysis in the muscle, dorsal root ganglia and spinal cord. NGF-induced LBP was characterized by long-lasting local and plantar mechanical hypersensitivity, cold hyperalgesia, decreased grip strength and wheel running activity, and time-dependent changes of neuropeptide and glial markers in the spinal cord. Interestingly, the exposure to CUS slightly worsened pain behavior, whereas vCRS primed and highly aggravated pain in this LBP model, by causing per se the intramuscular upregulation of endogenous NGF and increased spinal astrocyte expression.Our mouse model, particularly the combination of NGF injection and vCRS suggest that similar mechanisms are important in non-specific LBP and might help to investigate certain aspects of stress-induced exacerbation of pain.
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Chronic mechanical low back pain (cLBP) is a leading cause of disability and a major socio‐economic burden internationally. The lifetime prevalence of non‐specific LBP is approximately 84%, with the prevalence of cLBP at about 23%. Clinically available analgesic/adjuvant medications often provide inadequate pain relief in patients experiencing cLBP. Hence, the urgency for discovery of effective and better tolerated medications. Fourteen days after the induction of 5 shallow annular punctures (5X) in the lumbar intervertebral discs at L4/L5 and L5/L6 in male Sprague‐Dawley rats, mechanical hyperalgesia was fully developed in the lumbar axial deep tissues at L4/L5 (primary) and L1 (secondary). Importantly, mechanical allodynia in the hindpaws was absent. From day 28, we assessed the face validity of our mild to moderate LBP‐5X rat model using four clinically available analgesic/adjuvant drugs, namely gabapentin, morphine, meloxicam and amitriptyline relative to vehicle. Additionally, the anti‐hyperalgesic effects of J‐2156, a highly selective small molecule somatostatin type 4 receptor agonist was assessed. Single i.p. bolus doses of gabapentin and meloxicam at the highest doses tested (100 and 30 mg/kg respectively) alleviated secondary hyperalgesia (L1) but not primary hyperalgesia (L4/5). Morphine at 1 mg/kg alleviated both primary and secondary hyperalgesia in these tissues, whereas amitriptyline at the doses tested, lacked efficacy. These findings attest to the face validity of our model. J‐2156 at 10 and 30 mg/kg alleviated secondary hyperalgesia in the lumbar axial deep tissues at L1 with a non‐significant trend for relief of primary hyperalgesia in the corresponding tissues at L4/L5 in these animals
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Objective: About a third of patients with multiple sclerosis (MS) suffer from chronic and excruciating central neuropathic pain (CNP). The mechanism underlying CNP in MS is not clear, since previous studies are scarce and their results are inconsistent. Our aim was to determine whether CNP in MS is associated with impairment of the spinothalamic-thalamocortical pathways (STTCs) and/or increased excitability of the pain system. Design: Cross sectional study. Setting: General hospital. Subjects: 47 MS patients with CNP, 42 MS patients without CNP, and 32 healthy controls. Methods: Sensory testing included the measurement of temperature, pain, and touch thresholds and the thermal grill illusion (TGI) for evaluating STTCs function, and hyperpathia and allodynia as indicators of hyperexcitability. CNP was characterized using interviews and questionnaires. Results: The CNP group had higher cold and warm thresholds (p < 0.01), as well as higher TGI perception thresholds (p < 0.05), especially in painful body regions compared to controls, whereas touch and pain thresholds values were normal. The CNP group also had a significantly greater prevalence of hyperpathia and allodynia. Regression analysis revealed that whereas presence of CNP was associated with a higher cold threshold, CNP intensity, and the number of painful body regions were associated with allodynia and hyperpathia, respectively. Conclusions: CNP in MS is characterized by a specific impairment of STTC function; the innocuous thermal pathways, and by pain hyperexcitability. Whereas CNP presence is associated with STTC impairment, its severity and extent are associated with pain hyperexcitability. Interventions that reduce excitability level may therefore mitigate CNP severity.
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This systematic review synthesizes literature describing prevalence, characteristics, and prognosis of low back-related leg pain (LBLP) patients with neuropathic pain in primary care and/or similar settings. Inclusion and exclusion criteria were developed and used by independent reviewers to screen citations for eligibility. The initial search yielded 24,948 citations; after screening 12 studies were included. Neuropathic pain was identified using case ascertainment tools (n = 5), clinical history with examination (n = 4), and using LBLP samples assumed neuropathic (n = 3). Neuropathic pain prevalence varied from 19% to 80%. There was consistent evidence for higher back-related disability (n = 3), poorer health-related quality of life (n = 2), and some evidence for more severe depression (n = 2), anxiety (n = 3), and pain intensity (n = 4) in patients with neuropathic pain. Results were less consistent when cases were identified through clinical history with examination than those identified using case ascertainment tools. Prognosis (n = 1) of LBLP patients with neuropathic pain was worse compared with those without, in all outcomes (leg pain intensity, leg and back-related disability, self-reported general health) except back pain intensity. No studies described prognostic factors. This systematic review highlights the evidence gap in neuropathic pain in LBLP in primary care, especially with respect to prognosis. Perspective: Patients with LBLP may have neuropathic pain. This systematic review emphasizes the paucity of evidence describing the characteristics and prognosis of neuropathic pain in this patient population. Future research investigating prognosis of these patients with neuropathic pain is likely to contribute to better understanding and management.
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Unlabelled: Some forms of chronic pain are maintained or enhanced by activity in the sympathetic nervous system (SNS), but attempts to model this have yielded conflicting findings. The SNS has both pro- and anti-inflammatory effects on immunity, confounding the interpretation of experiments using global sympathectomy methods. We performed a "microsympathectomy" by cutting the ipsilateral gray rami where they entered the spinal nerves near the L4 and L5 DRG. This led to profound sustained reductions in pain behaviors induced by local DRG inflammation (a rat model of low back pain) and by a peripheral paw inflammation model. Effects of microsympathectomy were evident within one day, making it unlikely that blocking sympathetic sprouting in the local DRGs or hindpaw was the sole mechanism. Prior microsympathectomy greatly reduced hyperexcitability of sensory neurons induced by local DRG inflammation observed 4 d later. Microsympathectomy reduced local inflammation and macrophage density in the affected tissues (as indicated by paw swelling and histochemical staining). Cytokine profiling in locally inflamed DRG showed increases in pro-inflammatory Type 1 cytokines and decreases in the Type 2 cytokines present at baseline, changes that were mitigated by microsympathectomy. Microsympathectomy was also effective in reducing established pain behaviors in the local DRG inflammation model. We conclude that the effect of sympathetic fibers in the L4/L5 gray rami in these models is pro-inflammatory. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some chronic inflammatory pain conditions. Significance statement: Sympathetic blockade is used for many pain conditions, but preclinical studies show both pro- and anti-nociceptive effects. The sympathetic nervous system also has both pro- and anti-inflammatory effects on immune tissues and cells. We examined effects of a very localized sympathectomy. By cutting the gray rami to the spinal nerves near the lumbar sensory ganglia, we avoided widespread sympathetic denervation. This procedure profoundly reduced mechanical pain behaviors induced by a back pain model and a model of peripheral inflammatory pain. One possible mechanism was reduction of inflammation in the sympathetically denervated regions. This raises the possibility that therapeutic interventions targeting gray rami might be useful in some inflammatory conditions.
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Introduction Neuropathic low back-related leg pain (LBLP) can be a challenge to healthcare providers to diagnose and treat. Accurate diagnosis of neuropathic pain is fundamental to ensure appropriate intervention is given. However, to date there is no gold standard to diagnose neuropathic LBLP. Patient examination guidelines and screening tools have been developed and validated for the purpose of diagnosing neuropathic pain in LBLP; however, there has been no systematic review conducted to compare the diagnostic validity of these methods. Therefore, this systematic review will investigate the diagnostic utility of patient history, clinical examination and screening tool data to identify neuropathic pain in LBLP. Methods and analysis This protocol is informed and reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis-Protocols. CINAHL, EMBASE, MEDLINE, Web of Science, Cochrane Library, AMED, Pedro, PubMed, key journals and grey literature will be searched rigorously to find diagnostic accuracy studies investigating patient examination data to identify neuropathic pain in LBLP patients. Two independent reviewers will conduct the search, extract the data and assess risk of bias for included studies using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. The overall quality of included studies will be evaluated using Grading of Recommendations, Assessment, Development and Evaluation guidelines. A meta-analysis will be conducted if deemed appropriate. Otherwise, a narrative synthesis will be conducted. Ethics and dissemination No research ethics is required for this systematic review since patient data will not be collected. This review will help to inform healthcare professionals and researchers on the most effective means in which to diagnose neuropathic pain in LBLP. Results of this review will be submitted for publication in a peer-review journal and conference presentations. PROSPERO registration number CRD42019140861
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Nearly all amputees continue to feel their missing limb as if it still existed, and many experience chronic phantom limb pain (PLP). There is currently a broad consensus among investigators that the origin of these sensations is a top-down phenomenon, triggered by loss of sensory input and caused by maladaptive cortical plasticity. We tested the alternative hypothesis that PLP is primarily a bottom-up process, one due not to the loss of input but rather to exaggerated input, generated ectopically in axotomized primary afferent neurons in the dorsal root ganglia (DRG) that used to innervate the limb. In 31 amputees, the local anesthetic lidocaine was applied intrathecally and/or to the DRG surface (intraforaminal epidural block). This rapidly and reversibly extinguished PLP and also nonpainful phantom limb sensation. Control injections were ineffective. For intraforaminal block, the effect was topographically appropriate. This could also be demonstrated using dilute lidocaine concentrations that are sufficient to suppress DRG ectopia but not to block the propagation of impulses generated further distally in the nerve. PLP is driven primarily by activity generated within DRG. We recommend the DRG as a target for treatment of PLP and perhaps also other types of regional neuropathic pain. Keywords DRG; Ectopic firing; Electrogenesis; Intraforaminal; Neuropathic pain; Phantom limb pain Corresponding author contact information Corresponding author. Address: Department of Cell & Developmental Biology, Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel. Tel.: +972 2 6585085; fax: +972 2 6586027. Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.
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Hyperexcitability of the central nervous system (CNS) has been suggested to play an important role in the chronic pain experienced by osteoarthritis (OA) patients. A systematic review following PRISMA guidelines was performed to evaluate the existing evidence from the literature related to the presence of central sensitization (CS) in patients with OA.Electronic databases PubMed and Web of Science were searched to identify relevant articles using pre-defined keywords regarding CS and OA. Full-text clinical reports addressing studies of CS in human adults with chronic complaints due to osteoarthritis were included and screened for methodological quality by two independent reviewers. From the 40 articles that were initially eligible for methodological quality assessment, 36 articles achieved sufficient scores and therefore were discussed. The majority of these studies were case–control studies and addressed OA of the knee joint. Different subjective and objective parameters considered manifestations of CS, which have been previously reported in other chronic pain conditions such as whiplash or rheumatoid arthritis, were established in subjects with OA pain. Overall results suggest that, although peripheral mechanisms are involved in OA pain, hypersensitivity of the CNS plays a significant role in a subgroup of subjects within this population. Although the majority of the literature provides evidence for the presence of CS in chronic OA pain, clinical identification and treatment of CS in OA is still in its infancy, and future studies with good methodological quality are necessary.
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Central pain below the injury level after spinal cord injury is excruciating, chronic and resistive to treatment. Animal studies suggest that pretreatment may prevent central pain, but to date there are no measures to predict its development. Our aim was to monitor changes in the sensory profile below the lesion prior to the development of below-level central pain in order to search for a parameter that could predict its risk and to further explore its pathophysiology. Thirty patients with spinal cord injury and 27 healthy controls underwent measurement of warm, cold, heat-pain and touch thresholds as well as graphaesthesia, allodynia, hyperpathia and wind-up pain in intact region and in the shin and feet (below level). Patients were tested at 2–4 weeks, 1–2.5 months and 2.5–6 months after the injury or until central pain had developed. At the end of the follow-up, 46% of patients developed below-level central pain. During the testing periods, individuals who eventually developed central pain had higher thermal thresholds than those who did not and displayed high rates of abnormal sensations (allodynia and hyperpathia), which gradually increased with time until central pain developed. Logistic regressions revealed that the best predictor for the risk of below-level central pain was allodynia in the foot in the second testing session with a 77% probability (90.9% confidence). The results suggest that neuronal hyperexcitability, which may develop consequent to damage to spinothalamic tracts, precedes central pain. Furthermore, it appears that below-level central pain develops after a substantial build-up of hyperexcit-ability. To the best of our knowledge, this is the first systematic report establishing that neuronal hyperexcitability precedes central pain. Predicting the risk for central pain can be utilized to initiate early treatment in order to prevent its development.
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Background: Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Methods: Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Findings: Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350 000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Conclusions: Rates of YLDs per 100 000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Funding: Bill & Melinda Gates Foundation.
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This study aims to individualize the selection of drugs for neuropathic pain by examining the potential coupling of a given drug's mechanism of action with the patient's pain modulation pattern. The latter is assessed by the conditioned pain modulation (CPM) and temporal summation (TS) protocols. We hypothesized that patients with a malfunctioning pain modulation pattern, such as less efficient CPM, would benefit more from drugs augmenting descending inhibitory pain control than would patients with a normal modulation pattern of efficient CPM. Thirty patients with painful diabetic neuropathy received 1 week of placebo, 1 week of 30 mg/d duloxetine, and 4 weeks of 60 mg/d duloxetine. Pain modulation was assessed psychophysically, both before and at the end of treatment. Patient assessment of drug efficacy, assessed weekly, was the study's primary outcome. Baseline CPM was found to be correlated with duloxetine efficacy (r=0.628, P<.001, efficient CPM is marked negative), such that less efficient CPM predicted efficacious use of duloxetine. Regression analysis (R(2)=0.673; P=.012) showed that drug efficacy was predicted only by CPM (P=.001) and not by pretreatment pain levels, neuropathy severity, depression level, or patient assessment of improvement by placebo. Furthermore, beyond its predictive value, the treatment-induced improvement in CPM was correlated with drug efficacy (r=-0.411, P=.033). However, this improvement occurred only in patients with less efficient CPM (16.8±16.0 to -1.1±15.5, P<.050). No predictive role was found for TS. In conclusion, the coupling of CPM and duloxetine efficacy highlights the importance of pain pathophysiology in the clinical decision-making process. This evaluative approach promotes personalized pain therapy.
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Painful radiculopathies (RAD) and classical neuropathic pain syndromes (painful diabetic polyneuropathy, postherpetic neuralgia) show differences how the patients express their sensory perceptions. Furthermore, several clinical trials with neuropathic pain medications failed in painful radiculopathy. Epidemiological and clinical data of 2094 patients with painful radiculopathy were collected within a cross sectional survey (painDETECT) to describe demographic data and co-morbidities and to detect characteristic sensory abnormalities in patients with RAD and compare them with other neuropathic pain syndromes. Common co-morbidities in neuropathic pain (depression, sleep disturbance, anxiety) do not differ considerably between the three conditions. Compared to other neuropathic pain syndromes touch-evoked allodynia and thermal hyperalgesia are relatively uncommon in RAD. One distinct sensory symptom pattern (sensory profile), i.e., severe painful attacks and pressure induced pain in combination with mild spontaneous pain, mild mechanical allodynia and thermal hyperalgesia, was found to be characteristic for RAD. Despite similarities in sensory symptoms there are two important differences between RAD and other neuropathic pain disorders: (1) The paucity of mechanical allodynia and thermal hyperalgesia might be explained by the fact that the site of the nerve lesion in RAD is often located proximal to the dorsal root ganglion. (2) The distinct sensory profile found in RAD might be explained by compression-induced ectopic discharges from a dorsal root and not necessarily by nerve damage. These differences in pathogenesis might explain why medications effective in DPN and PHN failed to demonstrate efficacy in RAD.
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Adequate pain assessment is critical for evaluating the efficacy of analgesic treatment in clinical practice and during the development of new therapies. Yet the currently used scores of global pain intensity fail to reflect the diversity of pain manifestations and the complexity of underlying biological mechanisms. We have developed a tool for a standardized assessment of pain-related symptoms and signs that differentiates pain phenotypes independent of etiology. Using a structured interview (16 questions) and a standardized bedside examination (23 tests), we prospectively assessed symptoms and signs in 130 patients with peripheral neuropathic pain caused by diabetic polyneuropathy, postherpetic neuralgia, or radicular low back pain (LBP), and in 57 patients with non-neuropathic (axial) LBP. A hierarchical cluster analysis revealed distinct association patterns of symptoms and signs (pain subtypes) that characterized six subgroups of patients with neuropathic pain and two subgroups of patients with non-neuropathic pain. Using a classification tree analysis, we identified the most discriminatory assessment items for the identification of pain subtypes. We combined these six interview questions and ten physical tests in a pain assessment tool that we named Standardized Evaluation of Pain (StEP). We validated StEP for the distinction between radicular and axial LBP in an independent group of 137 patients. StEP identified patients with radicular pain with high sensitivity (92%; 95% confidence interval [CI] 83%-97%) and specificity (97%; 95% CI 89%-100%). The diagnostic accuracy of StEP exceeded that of a dedicated screening tool for neuropathic pain and spinal magnetic resonance imaging. In addition, we were able to reproduce subtypes of radicular and axial LBP, underscoring the utility of StEP for discerning distinct constellations of symptoms and signs. We present a novel method of identifying pain subtypes that we believe reflect underlying pain mechanisms. We demonstrate that this new approach to pain assessment helps separate radicular from axial back pain. Beyond diagnostic utility, a standardized differentiation of pain subtypes that is independent of disease etiology may offer a unique opportunity to improve targeted analgesic treatment.
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Chronic compression of the dorsal root ganglion (CCD) was produced in adult rats by implanting a stainless steel rod unilaterally into the intervertebral foramen, one rod at L(4) and another at L(5). Two additional groups of rats received either a sham surgery or an acute injury consisting of a transient compression of the ganglion. Withdrawal of the hindpaw was used as evidence of a nocifensive response to mechanical and thermal stimulation of the plantar surface. In addition, extracellular electrophysiological recordings of spontaneous discharges were obtained from dorsal root fibers of formerly compressed ganglia using an in vitro nerve-DRG-dorsal root preparation. The mean threshold force of punctate indentation and the mean threshold temperature of heating required to elicit a 50% incidence of foot withdrawal ipsilateral to the CCD were significantly lower than preoperative values throughout the 35 days of postoperative testing. The number of foot withdrawals ipsilateral to the CCD during a 20-min contact with a temperature-controlled floor was significantly increased over preoperative values throughout postoperative testing when the floor was 4 degrees C (hyperalgesia) and, to a lesser extent, when it was 30 degrees C (spontaneous pain). Stroking the foot with a cotton wisp never elicited a reflex withdrawal before surgery but did so in most rats tested ipsilateral to the CCD during the first 2 postoperative weeks. In contrast, the CCD produced no changes in responses to mechanical or thermal stimuli on the contralateral foot. The sham operation and acute injury produced no change in behavior other than slight, mechanical hyperalgesia for approximately 1 day, ipsilateral to the acute injury. Ectopic spontaneous discharges generated within the chronically compressed ganglion and, occurring in the absence of blood-borne chemicals and without an intact sympathetic nervous system, were recorded from neurons with intact, conducting, myelinated or unmyelinated peripheral nerve fibers. The incidence of spontaneously active myelinated fibers was 8.61% for CCD rats versus 0.96% for previously nonsurgical rats. We hypothesize that a chronic compression of the dorsal root ganglion after certain injuries or diseases of the spine may produce, in neurons with intact axons, abnormal ectopic discharges that originate from the ganglion and potentially contribute to low back pain, sciatica, hyperalgesia, and tactile allodynia.
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Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
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Study Design. The possibility to prevent nucleus pulposus-induced functional and structural nerve root injury by selective tumor necrosis factor-α inhibition was assessed in an experimental model in the pig spine. Objective. The objective of the study was to evaluate the role of tumor necrosis factor-α in the mediation of nucleus pulposus-induced nerve injury by using selective inhibition. Summary of Background Data. The cytokine tumor necrosis factor-α has been suggested to play a key role in the nerve root injury induced by local application of nucleus pulposus. However, previous studies have not been able to distinguish the effects between tumor necrosis factor-α and other disc-related cytokines because of the use of nonspecific cytokine inhibition. Methods. Autologous nucleus pulposus was harvested from a lumbar disc and applied to the porcine sacrococcygeal cauda equina. The pigs were simultaneously treated with two selective tumor necrosis factor-α inhibitors (etanercept n = 8 and infliximab n = 5), a heparin analogue (enoxaparin n = 5) or saline for control (n = 5). After 7 days the nerve conduction velocity over the application zone was determined and samples of the exposed nerve roots were collected for light microscopic evaluation. Results. The two tumor necrosis factor-α inhibitors prevented the reduction of nerve conduction velocity and also seemed to limit the nerve fiber injury, the intracapillary thrombus formation, and the intraneural edema formation. However, treatment with enoxaparin did not seem to be different from control regarding reduction of nerve conduction velocity or histologic changes. Conclusions. The data clearly indicate that tumor necrosis factor-α is involved in the basic pathophysiologic events leading to nerve root structural and functional changes after local application of nucleus pulposus. The study therefore provides a basic scientific platform with potential clinical implications regarding the use of anti-tumor necrosis factor-α medication as treatment in patients with disc herniation and sciatica.
Article
Intramuscular injection of nerve growth factor (NGF) is known to induce deep-tissue mechanical hyperalgesia. In this study it was hypothesised that daily intramuscular injections of NGF produce a progressive manifestation of soreness, mechanical hyperalgesia, and temporal summation of pain. In a double-blind placebo-controlled design, 12 healthy subjects were injected on three days with NGF into the tibialis anterior muscle and with isotonic saline on the contralateral side. Assessments were performed before and after the injections on days 0, 1, 2, and repeated on days 3, 6, and 10. The self-perceived muscle soreness was assessed on a Likert scale. Computer-controlled pressure algometry was used to assess the pressure pain thresholds (PPTs). Temporal summation of pain after repeated pressure stimulations was assessed by computer-controlled pressure algometry. The pain distribution following painful pressure stimulation was also recorded. Compared with baseline and isotonic saline the NGF injections caused (P<0.05): i) progressively increasing soreness scores from 3 h after the first injection until day 2 after which it remained increased, ii) decreased PPTs at days 1 to 3, iii) facilitated temporal summation of pressure pain at days 1 to 10, and iv) enlarged pressure-induced pain area after the injection on day 1 to day 6. The daily injections of NGF produced a progressive manifestation of muscle soreness, mechanical hyperalgesia, temporal summation of pressure pain, and pressure-induced pain distribution. These data illustrate that the prolonged NGF application affects peripheral and central mechanisms and may reflect process in musculoskeletal pain conditions.
Article
Objectives: There is no study on the role of prophylactic therapy on allodynia in patients with migraine. We report the predictors of allodynia in migraine and the effect of divalproate or amitriptyline in alleviating allodynia. Methods: Four hundred forty-eight consecutive patients with migraine diagnosed as per International Headache Society criteria were prospectively included. The presence of allodynia, its type and severity, and details of headache were enquired. Two hundred twenty-seven migraineurs were randomly allocated to amitriptyline (25 to 50 mg/d) or divalproate (500 to 750 mg/d). The improvement in allodynia and headache severity was recorded at 3 and 6 months. The side effects of the drugs were noted. Results: The median age of the patients was 32 years (range, 10 to 62 y) and 77.6% were females. 71.4% patients had allodynia; static mechanical in 90%, dynamic in 89.1%, and thermal in 17%. The allodynia was related to the duration of illness, frequency, severity of migraine, and female gender. Both divalproate and amitriptyline significantly reduced the frequency and severity of allodynia at 3 and 6 months compared with baseline though there was no group difference. The composite side effects were similar but valproate was discontinued in 5 patients because of polycystic ovary. Conclusions: 71.4% migraineurs had allodynia that was related to the duration, severity, frequency of migraine, and female gender. Divalproate and amitriptyline were equally effective in relieving allodynia.
Article
Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well-defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation. Ann Neurol 2000;47:614–624
Article
This topical update reports recent progress in the international effort to develop a more accurate and valid diagnostic criteria for complex regional pain syndrome (CRPS). The diagnostic entity of CRPS (published in the International Association for the Study of Pain’s Taxonomy monograph in 1994; International Association for the Study of Pain [IASP]) was intended to be descriptive, general, and not imply etiopathology, and had the potential to lead to improved clinical communication and greater generalizability across research samples. Unfortunately, realization of this potential has been limited by the fact that these criteria were based solely on consensus and utilization of the criteria in the literature has been sporadic at best. As a consequence, the full potential benefits of the IASP criteria have not been realized. Consensus-derived criteria that are not subsequently validated may lead to over- or underdiagnosis, and will reduce the ability to provide timely and optimal treatment. Results of validation studies to date suggest that the IASP/CRPS diagnostic criteria are adequately sensitive; however, both internal and external validation research suggests that utilization of these criteria causes problems of overdiagnosis due to poor specificity. This update summarizes the latest international consensus group’s action in Budapest, Hungary to approve and codify empirically validated, statistically derived revisions of the IASP criteria for CRPS.
Article
Nociceptor inputs can trigger a prolonged but reversible increase in the excitability and synaptic efficacy of neurons in central nociceptive pathways, the phenomenon of central sensitization. Central sensitization manifests as pain hypersensitivity, particularly dynamic tactile allodynia, secondary punctate or pressure hyperalgesia, aftersensations, and enhanced temporal summation. It can be readily and rapidly elicited in human volunteers by diverse experimental noxious conditioning stimuli to skin, muscles or viscera, and in addition to producing pain hypersensitivity, results in secondary changes in brain activity that can be detected by electrophysiological or imaging techniques. Studies in clinical cohorts reveal changes in pain sensitivity that have been interpreted as revealing an important contribution of central sensitization to the pain phenotype in patients with fibromyalgia, osteoarthritis, musculoskeletal disorders with generalized pain hypersensitivity, headache, temporomandibular joint disorders, dental pain, neuropathic pain, visceral pain hypersensitivity disorders and post-surgical pain. The comorbidity of those pain hypersensitivity syndromes that present in the absence of inflammation or a neural lesion, their similar pattern of clinical presentation and response to centrally acting analgesics, may reflect a commonality of central sensitization to their pathophysiology. An important question that still needs to be determined is whether there are individuals with a higher inherited propensity for developing central sensitization than others, and if so, whether this conveys an increased risk in both developing conditions with pain hypersensitivity, and their chronification. Diagnostic criteria to establish the presence of central sensitization in patients will greatly assist the phenotyping of patients for choosing treatments that produce analgesia by normalizing hyperexcitable central neural activity. We have certainly come a long way since the first discovery of activity-dependent synaptic plasticity in the spinal cord and the revelation that it occurs and produces pain hypersensitivity in patients. Nevertheless, discovering the genetic and environmental contributors to and objective biomarkers of central sensitization will be highly beneficial, as will additional treatment options to prevent or reduce this prevalent and promiscuous form of pain plasticity.
Article
We have developed a model in which inflammation contiguous to and within a dorsal root ganglion (DRG) was generated by local application of complete Freund's adjuvant (CFA) to the L4 lumbar spinal nerve as it exits from the intervertebral foramen. The periganglionic inflammation (PGI) elicited a marked reduction in withdrawal threshold to mechanical stimuli and an increase in heat pain sensitivity in the ipsilateral hindpaw in the absence of any hindpaw inflammation. The pain sensitivity appeared within hours and lasted for a week. The PGI also induced a prominent increase in IL-1beta and TNF-alpha levels in the DRG and of cyclooxygenase-2 (COX-2) expression in neurons and satellite cells. A selective COX-2 inhibitor reduced the PGI-induced hyperalgesia. We also show that IL-1beta induces COX-2 expression and prostaglandin release in DRG neurons in vitro in a MAP kinase-dependent fashion. The COX-2 induction was prevented by ERK and p38 inhibitors. We conclude that periganglionic inflammation increases cytokine levels, including IL-1beta, leading to the transcription of COX-2 and prostaglandin production in the affected DRG, and thereby to the development of a dermatomally distributed pain hypersensitivity.
Article
Single-unit exploration of the dorsal horn of segments L4-S2 of unanesthetized cats with the neuraxis transected at lower thoracic levels reveals a somototopic organization in the horizontal plane. The dorsal horn dermatomes correspond closely to the dermatomes of the corresponding dorsal roots, and the ML gradient is equally well described by two different projection schemes: a distoproximal gradient and a ventrodorsal one (5, 33). There is no evidence of segmental discontinuity of the map. As is the case in other nuclear regions of the CNS, the relative area devoted to projections from the foot is disproportionately large relative to the area devoted to skin regions of similar size which are located more proximally on the limb. From our data, and from the close correspondence to anatomical data obtained by others, we suggest that at least some cutaneous afferent fibers from a given skin area project directly to any dorsal horn region where that skin area is represented. This assumption, together with the organization of the dorsal horn map, yields a model which predicts a precise somatotopic organization of presynaptic neuropil in the substantia gelatinosa.
Article
The McGill Pain Questionnaire consists primarily of 3 major classes of word descriptors--sensory, affective and evaluative--that are used by patients to specify subjective pain experience. It also contains an intensity scale and other items to determine the properties of pain experience. The questionnaire was designed to provide quantitative measures of clinical pain that can be treated statistically. This paper describes the procedures for administration of the questionnaire and the various measures that can be derived from it. The 3 major measures are: (1) the pain rating index, based on two types of numerical values that can be assigned to each word descriptor, (2) the number of words chosen; and (3) the present pain intensity based on a 1-5 intensity scale. Correlation coefficients among these measures, based on data obtained with 297 patients suffering several kinds of pain, are presented. In addition, an experimental study which utilized the questionnaire is analyzed in order to describe the nature of the information that is obtained. The data, taken together, indicate that the McGill Pain Questionnaire provides quantitative information that can be treated statistically, and is sufficiently sensitive to detect differences among different methods to relieve pain.
Article
1. Capsaicin, the algesic substance in chilli peppers, was injected intradermally in healthy human subjects. A dose of 100 micrograms given in a volume of 10 microliters caused intense pain lasting for a few minutes after injection and resulted in a narrow area of hyperalgesia to heat and a wide surrounding area of hyperalgesia to mechanical stimuli (stroking) lasting for 1-2 h. 2. Nerve compression experiments with selective block of impulse conduction in myelinated (A) but not in unmyelinated (C) fibres indicated that afferent signals in C fibres contributed to pain from capsaicin injection and to heat hyperalgesia, whereas conduction in afferent A fibres was necessary for the perception of mechanical hyperalgesia. 3. Electrical intraneural microstimulation normally eliciting non-painful tactile sensations was accompanied by pain when the sensation was projected to skin areas within the region of mechanical hyperalgesia induced by capsaicin injection. 4. The threshold for pain evoked by intraneural microstimulation was reversibly lowered and pain from suprathreshold stimulation was exaggerated during the period of mechanical hyperalgesia, regardless of lidocaine anaesthesia of the cutaneous innervation territory of the stimulated fibres. 5. The results indicate that hyperalgesia to stroking on a skin area surrounding a painful intradermal injection of capsaicin is due to reversible changes in the central processing of mechanoreceptive input from myelinated fibres which normally evoke non-painful tactile sensations.
Article
1. Psychophysical studies were made, in humans, of the sensory characteristics and underlying mechanisms of the hyperalgesia (often termed "secondary hyperalgesia") that occurs in uninjured skin surrounding a local cutaneous injury. The hyperalgesia was characterized by lowered pain thresholds and enhanced magnitude of pain to normally painful stimuli. The "injury" was produced by a single intradermal injection of 10 microliters of 100 micrograms of capsaicin, the algesic substance in hot chili peppers. 2. On injection of capsaicin into the volar forearm, the subjects experienced intense burning pain, accompanied immediately by the formation of three areas of hyperalgesia surrounding the injection site. The largest mean area (55 cm2) was hyperalgesic to a normally painful punctate stimulation of the skin. Nested within this was an area of tenderness to gentle stroking (38 cm2) and a much smaller area of hyperalgesia to heat (2 cm2). An area of analgesia to pinprick, approximately 4 mm in diameter and centered on the injection site, developed within minutes and typically disappeared within 24 h. The hyperalgesia to heat and to stroking disappeared within 1-2 h, whereas the hyperalgesia to punctate stimuli, although gradually decreasing in area, lasted from 13 to 24 h. 3. The radial spread of the mechanical hyperalgesia (to punctate and stroking stimuli) away from the injury was dependent on neural activity and not produced, for example, by algesic substances transported away from the injury. The injection of capsaicin into a small area of anesthetized skin did not produce hyperalgesia in the surrounding, unanesthetized skin. Also, the hyperalgesia in normal skin readily crossed a tight arm band that blocked the circulation of blood and lymph. 4. The spread of mechanical hyperalgesia away from the injury was peripherally mediated via cutaneous nerve fibers because it was blocked by a thin mediolateral strip of cutaneous anesthesia placed 1 cm away from the capsaicin injection site. Hyperalgesia developed normally on the capsaicin side of the strip but not on the other side. 5. Heat stimulation of the skin that produced pain that was equivalent in magnitude and time course to that produced by an injection of capsaicin (10 micrograms) resulted in much smaller areas of mechanical hyperalgesia. It was postulated that there exist special chemosensitive primary afferent nerve fibers that are more effective in producing mechanical hyperalgesia than are the known thermo- and mechanosensitive nociceptive nerve fibers. 6. Once developed, the mechanical hyperalgesia became only partially dependent on peripheral neural activity originating at the site of injury.(ABSTRACT TRUNCATED AT 400 WORDS)
Article
Ectopically generated and antidromically conducted nerve impulses were recorded in 5 patients with tungsten microelectrodes inserted into skin nerve fascicles. All patients had mainly positive sensory symptoms and reported paresthesiae which could be provoked by different maneuvers which suggested increased mechanosensitivity of the primary sensory neurons at different anatomic levels. Ectopic multiunit nerve activity correlating in intensity and time course to the positive sensory symptoms was recorded: when Tinel's sign was elicited in a patient with entrapment of the ulnar nerve at the elbow, when paresthesiae were provoked by elevation of the arm in a patient with symptoms consistent with a thoracic outlet syndrome, when paresthesiae were evoked by straining during chin-chest maneuver in a patient with an S1 syndrome due to a herniated lumbar disc, when a painful Lasegue's sign occurred during the straight-leg raising test in a patient with an S1 syndrome due to root fibrosis, and when Lhermitte's sign was elicited by neck flexion in a patient with multiple sclerosis. The sites for the ectopic impulse generation in these cases are suggested to be peripheral nerve, brachial plexus, dorsal root or dorsal root ganglion and dorsal columns. The paresthesiae were non-painful except in the patient with Lasegue's sign and the ectopic impulses were probably recorded from large myelinated afferent fibers.
Article
Characteristics of primary (within the area of injury) and secondary (outside the area of injury) hyperalgesia were determined after a heat injury applied to the glabrous skin of the hand in 8 human volunteers. The heat injury consisted of two burns (53 degrees C, 30 s) applied over an area 7.5 mm in diameter separated (centre to centre) by a 2 cm interval. Following the injury, a zone of hyperalgesia to mechanical stimuli measuring 20.1 +/- 3.6 cm2 (mean +/- SEM) developed in an area surrounding and including the burns. Within this zone, the pain threshold for mechanical stimuli decreased significantly by a similar amount for all areas tested (12.0 +/- 1.1 bars to 5.2 +/- 0.5 bars). Hyperalgesia to heat occurred only within the area of the burns. The heat pain threshold decreased and total ratings of heat pain increased significantly. In contrast, there was decreased pain to heat stimuli between the two burn sites, and no change in painfulness of the heat stimuli at other areas within the zone of hyperalgesia to mechanical stimuli. Particularly notable was the coexistence of hypalgesia to heat stimuli and hyperalgesia to mechanical stimuli in the uninjured region between the two burn sites. These results indicate that the characteristics of primary and secondary hyperalgesia differ and also suggest that the mechanism for hyperalgesia to mechanical and thermal stimuli differ.
Article
The recently proposed animal model of lumbar radiculopathy was used to investigate behavioral consequences and histologic changes in spinal nerve roots, dorsal root ganglia, and spinal nerves after the L4, L5, and L6 nerve roots were loosely ligated with either silk or chromic gut sutures in an attempt to better understand the pathophysiologic mechanisms that give rise to pain associated with lumbar radiculopathy. Little is known about the pathophysiologic mechanisms that give rise to pain associated with lumbar radiculopathy. The recently proposed animal model of unilateral lumbar radiculopathy, which demonstrated an association with motor paresis and thermal hyperalgesia of the affected hind limb and showed evidence of spontaneous pain has been demonstrated, may serve as a vehicle to allow direct investigation of the nature of the pathophysiological mechanisms associated with lumbar radiculopathy. Three distinct treatments of the nerve roots were initially investigated: 1) a sham intervention, where the surgery simply exposed the nerve roots and dorsal root ganglion followed by standard closing procedures; 2) 4-0 silk ligature, where two loose ligatures of 4-0 silk were placed around the nerve roots; and 3) 4-0 chromic gut 2, where four 0.3 cm pieces of 4-0 chromic gut were laid adjacent to the nerve roots and secured by two loose ligatures of 4-0 chromic gut. ANOVA techniques were used to test for differential effects across time for the three treatment groups in terms of animal function. A qualitative analysis of the histology of the ipsilateral and contralateral nerve roots, dorsal root ganglia, and spinal nerves was done to correlate histologic changes with behavioral changes. Behavioral results were consistent with the previous study. Rats treated with chromic gut, but not silk, reliably demonstrated a prolonged thermal hyperalgesia that was maximal 2 weeks after surgery and lasted for up to 12 weeks. These behavioral changes, however, were not correlated with histologic changes in myelinated fiber content in the L4, L5, and L6 nerve roots, dorsal root ganglia and spinal nerves, the ipsilateral spinal nerved, dorsal root ganglia, and nerve roots of rates ligated with silk or chromic gut showed similar, significant, decreased in the number of large diameter myelinated fibers. These results suggest that mechanical constriction of the L4, L5, and L6 spinal nerve roots, as evidenced by a loss of myelinated fibers, is not sufficient to produce the behavioral effects associated with this model of lumbar radiculopathy. It is hypothesized that chemical factors from the chromic gut play a role in the pathophysiology and development of the behavioral, but not histological, changes in this model of lumbar radiculopathy.
Article
Tumour necrosis factor-alpha, a pro-inflammatory cytokine, is expressed endoneurially following a variety of local and systemic pathophysiological insults which give rise to pain. We administered tumour necrosis factor-alpha to pentobarbital-anaesthetized rats, either topically along a restricted portion of the sciatic nerve or injected subcutaneously within the distribution of the sural nerve. Single nociceptive primary afferent fibres were assessed for ectopic discharge and receptor sensitization. Low concentrations (0.001-0.01 ng/ml) of tumour necrosis factor-alpha applied along the nerve elicited a dose-dependent, rapid onset (1-3 min) increase in discharge; higher concentrations led to reduced firing rates. C-fibres developed higher mean firing frequencies than A delta-fibres. Bursting frequency in both fibre types reached several (6) Hz. No change in mechanical threshold was observed. Intradermal injection (50 pg in 50 microliters) led to ectopic discharge and a decrease in mechanical threshold; these effects developed at different rates, suggesting multiple actions of the cytokine. Our data suggest that acute application of tumour necrosis factor-alpha to the axon can lead to aberrant electrophysiologic activity independent of peripheral receptor involvement. This low level of ectopic firing of nociceptive axons may produce wind-up in dorsal horn neurons or may, by itself, be interpreted as pain.
Article
Under anesthesia and sterile surgery, a small stainless steel rod (4 mm in length and 0.5-0.8 mm in diameter) was inserted into the L5 intervertebral foramen in the rat, developing intervertebral foramen stenosis and hence producing a chronic steady compression of the dorsal root ganglion (DRG). The hind paw on the injured side exhibited a significant reduction in the latency of foot withdrawal to noxious heat and manifested a persistent heat hyperalgesia 5-35 days after surgery. Injection of 1% carrageenan into the intervertebral foramen, presumably causing inflammation of the DRG, also produced hyperalgesia to heat on the hind paw of the injured side 5-21 days after surgery. Extracellular electrophysiological recordings from myelinated dorsal root fibers were performed in vivo. Spontaneous activity was present in 21.5% of the fibers recorded from DRG neurons injured with chronic compression in contrast to 1.98% from uninjured DRG neurons. The pattern of spontaneous activity was periodic and bursting in 75.3% of the spontaneously active fibers. These neurons had a greatly enhanced sensitivity to mechanical stimulation of the injured DRG and a prolonged after discharge. In response to TEA, topically applied to the DRG, excitatory responses were evoked in the injured, but not the uninjured, DRG neurons. Application of this experimental model may further our understanding of the neural mechanisms by which chronic compression of DRG induces low back pain and sciatica.
Article
Recent animal studies on the mechanism of migraine show that intracranial pain is accompanied by increased periorbital skin sensitivity. These findings suggest that the pathophysiology of migraine involves not only irritation of meningeal perivascular pain fibers but also a transient increase in the responsiveness (ie, sensitization) of central pain neurons that process information arising from intracranial structures and skin. The purpose of this study was to determine whether the increased skin sensitivity observed in animal also develops in humans during migraine attacks. Repeated measurements of mechanical and thermal pain thresholds of periorbital and forearm skin areas in the absence of, and during, migraine attacks enabled us to determine the occurrence of cutaneous allodynia during migraine. Cutaneous allodynia is pain resulting from a nonnoxious stimulus to normal skin. In 79% of the patients, migraine was associated with cutaneous allodynia as defined, and in 21% of the patients it was not. The cutaneous allodynia occurred either solely within the referred pain area on the ipsilateral head, or within and outside the ipsilateral head. Cutaneous allodynia in certain well-defined regions of the skin during migraine is an as yet unreported neurological finding that points to hyperexcitability of a specific central pain pathway that subserves intracranial sensation.
Article
The possibility to prevent nucleus pulposus-induced functional and structural nerve root injury by selective tumor necrosis factor-alpha inhibition was assessed in an experimental model in the pig spine. The objective of the study was to evaluate the role of tumor necrosis factor-alpha in the mediation of nucleus pulposus-induced nerve injury by using selective inhibition. The cytokine tumor necrosis factor-alpha has been suggested to play a key role in the nerve root injury induced by local application of nucleus pulposus. However, previous studies have not been able to distinguish the effects between tumor necrosis factor-alpha and other disc-related cytokines because of the use of nonspecific cytokine inhibition. Autologous nucleus pulposus was harvested from a lumbar disc and applied to the porcine sacrococcygeal cauda equina. The pigs were simultaneously treated with two selective tumor necrosis factor-alpha inhibitors (etanercept n = 8 and infliximab n = 5), a heparin analogue (enoxaparin n = 5) or saline for control (n = 5). After 7 days the nerve conduction velocity over the application zone was determined and samples of the exposed nerve roots were collected for light microscopic evaluation. The two tumor necrosis factor-alpha inhibitors prevented the reduction of nerve conduction velocity and also seemed to limit the nerve fiber injury, the intracapillary thrombus formation, and the intraneural edema formation. However, treatment with enoxaparin did not seem to be different from control regarding reduction of nerve conduction velocity or histologic changes. The data clearly indicate that tumor necrosis factor-alpha is involved in the basic pathophysiologic events leading to nerve root structural and functional changes after local application of nucleus pulposus. The study therefore provides a basic scientific platform with potential clinical implications regarding the use of anti-tumor necrosis factor-alpha medication as treatment in patients with disc herniation and sciatica.
Article
Dermatome maps are commonly used in clinical neurology. These maps are valuable for the localization of varied sensory phenomena in patients with neurological disorders. The methods used in the construction of the classic maps by Sir Henry Head, Sir Charles Sherrington, Otfrid Foerster, and Jay Keegan and Frederic Garrett are of historical interest and are relevant to the current understanding of dermatome anatomy and physiology. In particular, the work of Derek Denny-Brown and his colleagues demonstrates that patterns of dermatomal sensory loss depend on the anatomical and physiological characteristics of large regions of nervous tissue, multiple adjacent dorsal ganglia, and the nearby caudal and rostral spinal cord.
Article
Neuropathic pain is often severe and resistant to pharmacological treatment. The aims of the present study were to assess the analgesic effect of ketamine and lidocaine and to investigate if measurement of different variables of sensibility could be used to identify responders. We also wanted to study if treatment resulted in changes of sensibility. Twelve patients with long-lasting peripheral neuropathic pain of traumatic origin were included. The effects of ketamine hydrochloride (Ketalar, Parke Davis) 0.4 mg/kg and lidocaine hydrochloride (Xylocain, Astra) 2.5 mg/kg were investigated. Saline was used as placebo. The intensity of continuous pain was measured by a visual analogue scale (VAS). Warm and cold perception as well as heat and cold pain thresholds were assessed. Sensibility to touch was also tested. Systemic plasma concentrations of lidocaine and ketamine were assessed. The mean reduction in VAS-scores was 55%, 34% and 22% for ketamine, lidocaine and placebo, respectively. A significant difference was registered between ketamine and placebo (P = 0.009). Response to treatment (50% reduction in VAS-score during infusion) was recorded in 7/12 in the ketamine, 4/12 in the lidocaine and 2/12 in the placebo group. Quantitative sensory testing (QST) of thermal sensitivity and sensory tests for mechanical stimuli could not separate responders from non-responders and neither were the results from these assessments changed by the infusion of the drugs. Lidocaine and particularly ketamine were associated with frequent side-effects, the most common being somnolence and dizziness. Ketamine showed a significant analgesic effect. The clinical usefulness is, however, limited by disturbing side-effects.
Article
Peripheral neuropathic pain syndromes (PNPS) are difficult to treat because commonly used analgesics are often ineffective when, for example, touch-evoked allodynia, hyperalgesia, and pain paroxysms are present. To investigate whether lidocaine patch 5% treatment is also effective in postherpetic neuropathy (PHN) and in other PNPS, 40 patients with various forms and localizations of PNPS completed a prospective, randomized, placebo-controlled, two-way, cross-over study in three medical hospitals. Patients suffering from pain in a localized skin area with intensity above 40 mm visual analog scale (VAS) and a stable consumption of pain medication were included in this study. The study was divided into four phases: 3-day run-in phase, treatment phase 1, wash-out period, and treatment phase 2, each lasting 1 week. At the discretion of the patients, up to four patches (covering a maximum of 560 cm2) were applied onto the maximally painful area for 12 consecutive hours daily, always either by day or at night. Throughout the four phases, ongoing pain, allodynia, quality of neuropathic symptoms, quality of sleep, and adverse events were assessed. When, after the wash-out period, the pain intensity scores did not return to the pre-treatment values (+/-20%), these patients were excluded from the study. The present study revealed that, as an add-on therapy, the lidocaine patch 5% was clearly effective in reducing ongoing pain (P=0.017) and allodynia (P=0.023) during the first 8 h after application and that the patches also worked well over a period of 7 days (P=0.018) in diverse focal PNPS. Calculation of the numbers needed to treat (NNT) to obtain one patient with more than 50% relief of ongoing pain revealed that the NNT of 4.4 in the present study compared reasonably well with other studies of PHN, such as topically applied capsaicin (NNT: 5.3-infinity) or systemic treatment with gabapentin (NNT: 3.2-5.0).
Article
To investigate the effects of IV lidocaine on spontaneous and evoked pain (allodynia and hyperalgesia) due to peripheral nerve injury (postherpetic neuralgia or nerve trauma) using quantitative sensory testing. The authors randomized 22 patients to receive lidocaine 5 mg/kg IV during 30 minutes or placebo in a double-blind crossover design and 16 patients subsequently received mexiletine on an open basis titrated from 400 to 1,000 mg per day (mean 737 mg/day). Lidocaine induced a significant decrease in ongoing pain for up to 6 hours with a peak effect 60 to 120 minutes postinjection. The drug also decreased mechanical dynamic allodynia and static (punctate) mechanical allodynia/hyperalgesia, but not thermal allodynia and hyperalgesia. The effects of lidocaine and mexiletine on spontaneous pain intensity were significantly higher in patients with concomitant mechanical allodynia in comparison with those without allodynia. These data indicate modality-specific antihyperalgesic effects of IV lidocaine in patients with peripheral nerve injury. Patients with mechanical allodynia may be good candidates for treatment with local anesthetic-like drugs and possibly with other sodium-channel blockers.
Article
After transection of the inferior alveolar nerve (IAN), the whisker pad area, which is innervated by the infraorbital nerve (ION) that was not injured, showed hypersensitivity to mechanical stimulation. Two days after IAN transection, threshold intensity for escape behavior to mechanical stimulation of the ipsilateral whisker pad area was less than 4.0 g, indicating mechanical allodynia. A total of 68 single fiber discharges were recorded from ION fibers at 3 days after IAN transection. The responses of C- and A-fibers were classified according to their conduction velocity. The C-fiber activities were not affected by IAN transection, whereas A-fiber activities were significantly enhanced by IAN transection as indicated by an increase in background activity and mechanically evoked response. Since the A-fiber responses were significantly affected by IAN transection, patch clamp recording was performed from middle to large diameter retrogradely labeled and acutely dissociated trigeminal ganglion (TRG) neurons. The I(K) (sustained) and I(A) (transient) currents were significantly smaller and hyperpolarization-activated current (I(h)) was significantly larger in TRG neurons of rats with IAN transection as compared to those of naive rats. Furthermore, current injection into TRG neurons induced high frequency spike discharges in rats with IAN transection. These data suggest that changes in K(+) current and I(h) observed in the uninjured TRG neurons reflect an increase in excitability of TRG neurons innervated by the ION after IAN transection, resulting in the development of mechano-allodynia in the area adjacent to the injured IAN innervated region.
Article
Postoperative pain is characterized by spontaneous pain at the surgical site and increased pain due to movements. To study postoperative pain mechanisms, we investigated discharge properties of mechano-heat sensitive C-fiber afferents innervating the rat glabrous hindpaw skin 1 day after plantar incision. Behaviors indicating spontaneous pain, heat and mechanical hyperalgesia were present 1 day after incision. Recording of afferents using in vitro glabrous skin-nerve preparation showed that more C-fibers from the incision had spontaneous discharge than control rats. The spontaneously discharging fibers from incised rats had lower heat response threshold compared with fibers without spontaneous activity. In all fibers less than 2 mm from the incision, an increased percentage responded to lower temperatures (35-41 degrees C), the mean heat response threshold was 3.1 degrees C less, the stimulus-response function for heat evoked response was shifted to the left and the total number of impulses in response to a 33-48 degrees C heat stimulus was increased. Heat responses of C-fibers more than 2 mm from the incision, however, were not different from control. The mean mechanical response thresholds, measured by a servo force-controlled stimulator, were not different between groups. The total spikes evoked at supra-threshold mechanical stimulation were not increased in afferents from the incision. In conclusion, 1 day after incision, when behaviors indicating spontaneous pain, heat and mechanical hyperalgesia are present, C-fibers close to incision showed spontaneous discharge and sensitization to heat but not to mechanical stimuli, in vitro.
Article
This study examined whether or not the properties of cutaneous nociceptive fibers are altered in the neuropathic state by comparing lumbars 5 and 6 spinal nerve ligation (SNL) rats with sham-operated controls. The rats with the unilateral SNL developed mechanical allodynia in the ipsilateral hind limb, whereas the sham group did not. Two to 5 weeks after the neuropathic or sham surgery, rats were subjected to single fiber-recording experiments to examine the properties of afferent fibers in the sural and plantar nerves. A total of 224 afferents in the C- and Adelta-ranges were characterized in the neuropathic and sham groups. Spontaneous activity was observed in 16 of 155 fibers in the neuropathic group and one of 69 fibers in the sham group. The response threshold of both the C- and Adelta-fibers to mechanical stimuli was lower in the neuropathic group than the sham group. The afferent fibers responsive to heat stimuli were all C-fibers, and none were Adelta-fibers. The response threshold of the C-fibers to the heat stimuli was lower in the neuropathic group than the sham group. The magnitude of the responses of both C- and Adelta-fibers to the suprathreshold intensity of the mechanical stimulus was greater in the neuropathic group than the sham group. However, the magnitude of the responses of C-fibers to the suprathreshold intensity of the heat stimulus in the neuropathic group was not different from that in the sham group. These results suggest that after a partial peripheral nerve injury, the nociceptors on the skin supplied by an uninjured nerve become sensitized to both mechanical and heat stimuli. This nociceptor sensitization can contribute to neuropathic pain.
Article
Synchronous activity of large populations of neurons shapes neuronal networks during development. However, re-emergence of such activity at later stages of development could severely disrupt the orderly processing of sensory information, e.g. in the spinal dorsal horn. We used Ca2+ imaging in spinal cord slices of neonatal and young rats to assess under which conditions synchronous activity occurs in dorsal horn. No spontaneous synchronous Ca2+ transients were detected. However, increasing neuronal excitability by application of 4-aminopyridine after pretreatment of the slice with blockers of (RS)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate, gamma-aminobutyric acid (GABA)(A) and glycine receptors evoked repetitive Ca2+ waves in dorsal horn. These waves spread mediolaterally with a speed of 1.0 +/- 0.1 mm/s and affected virtually every dorsal horn neuron. The Ca2+ waves were associated with large depolarizing shifts of the membrane potential of participating neurons and were most likely synaptically mediated because they were abolished by blockade of action potentials or N-methyl-D-aspartate (NMDA) receptors. They were most pronounced in the superficial dorsal horn and absent from the ventral horn. A significant proportion of the Ca2+ waves spread to the contralateral dorsal horn. This seemed to be enabled by disinhibition as primary afferent-induced dorsal horn excitation crossed the midline only when GABA(A) and glycine receptors were blocked. Interestingly, the Ca2+ waves occurred under conditions where AMPA/kainate receptors were blocked. Thus, superficial dorsal horn NMDA receptors are able to sustain synchronous neuronal excitation in the absence of functional AMPA/kainate receptors.
Article
This study measured mechanical sensation and pain thresholds in the cutaneous field overlying the knee joints of rheumatoid arthritis (RA; N = 27) and osteoarthritis (OA; N = 28) patients, compared with age- and weight-matched normal control subjects (Norm; N = 27) by using graded von Frey monofilaments. A visual analog scale (VASpain), cutaneous joint temperature and circumference were measured for subjective ongoing pain and inflammation. Compared to Norm, RA and OA groups had (1) significantly higher VASpain scores, joint circumferences and (RA only) surface temperatures, (2) significantly increased average thresholds for innocuous mechanical sensation (0.014 +/- 0.003 vs 0.077 +/- 0.035 and 0.123 +/- 0.043 g, respectively) indicative of hypoesthesia and (3) significantly decreased pain thresholds, indicative of mechanical allodynia (446.683 +/- 0 vs 285.910 +/- 40.012 and 322.681 +/- 34.521 g for Norm vs RA and OA, respectively). Intrapatient joint temperature, circumference, and pain threshold were significantly correlated in RA. The highest scores in average mechanical sensation mapped to the same grid region as the lowest scores in average pain thresholds in RA and OA patients. The simultaneous hypoesthesia and allodynia, with paradoxical decrease in sensation and increased pain thresholds may reflect peripheral and central alterations in neuronal responsiveness to mechanical stimulation and suggests activation of a descending inhibitory system.
Article
The association between lumbar facet joint inflammation and radiculopathy was investigated using behavioral, histologic, and immunohistochemical testing in rats. To develop a rat model of lumbar facet joint inflammation and ascertain whether facet joint inflammation induces radiculopathy using this model. Both mechanical and chemical factors have been identified as important for inducing radiculopathy. In lumbar spondylosis, facet joint osteophytes may contribute to nerve root compression, which may induce radiculopathy. Furthermore, inflammation may occur in the facet joint, as in other synovial joints. Inflamed synovium may thus release inflammatory cytokines and induce nerve root injury with subsequent radiculopathy. A piece of gelatin sponge containing complete adjuvant was inserted into the L5-L6 facet joint in rats (arthritis group). Saline was used in the control group. Mechanical allodynia was determined using the von Frey test. Inflammatory cells infiltrating the epidural space were counted, and changes in cartilage were assessed histologically. Tumor necrosis factor (TNF)-alpha-immunoreactive cells in the L5 dorsal root ganglion were counted. Mechanical allodynia was observed in the arthritis group from day 3, gradually recovering during the observation period. Significantly larger numbers of inflammatory cells had infiltrated the epidural space by days 3 and 7 in the arthritis group than in controls. Numbers of TNF-alpha-immunoreactive cells were significantly increased at days 1 and 3 in the arthritis group compared with controls. Predominantly small nociceptive neurons were stained. When inflammation was induced in a facet joint, inflammatory reactions spread to nerve roots, and leg symptoms were induced by chemical factors. These results support the possibility that facet joint inflammation induces radiculopathy.
Article
To assess whether pseudoradicular low-back pain may be associated with subclinical sensory deficits in the distal extremity, we applied the quantitative sensory testing protocol of the German Research Network on Neuropathic Pain (DFNS) in 15 patients with pseudoradicular pain distribution. Sixteen age- and gender-matched healthy control subjects as well as 12 patients with radicular pain syndromes (L4-S1) were studied with the same protocol. Radicular pain was diagnosed using clinical criteria (pain radiation beyond the knee, motor-, sensory-, or reflex deficits, positive Laségue's test). Z-score QST profiles revealed a selective loss of vibration detection, detection of v. Frey hair contact, and cold detection in the affected dermatomes in the radicular pain group. The contralateral dermatome was also affected, but to a lesser degree. In patients with pseudoradicular pain, the sensory profile was similar, but sensory loss was less pronounced than in the radicular pain patients. There was no significant difference between the two patient groups. Vibration detection was the most sensitive parameter with 73% abnormal values in radicular and 47% in pseudoradicular cases. These data verified the sensitivity of QST to detect sensory loss in radicular compression syndromes, and support a neuropathic component in low-back pain with radiculopathy. In contrast to some central pain syndromes this sensory loss involved predominantly large fiber functions. The subclinical sensory loss in pseudoradicular cases suggests that these patients may also have a neuropathic component of their chronic pain. The spatial incongruence of pain and sensory loss in pseudoradicular pain, however, may also indicate that the two are not causally related.