Screening of neuropathic pain components in patients with chronic back pain associated with nerve root compression: a prospective observational pilot study (MIPORT)

ABSTRACT

Objective: Chronic back pain is characterized by a combination of neuropathic and nociceptive mechanisms of pain generation. The prevalence of the neuropathic pain component is unknown. Thus, in the context of an explorative study, we aimed to determine the prevalence of signs and symptoms indicating neuropathic pain in adult patients treated by orthopaedists. We also aimed to assess the usefulness of handheld computers (PDAs) in data collection.

Methods: Prospective epidemiological study in 18 orthopaedic practices or centres throughout Germany. Physician and patient questionnaires (paper/pencil or on handheld computers, PDAs) for patients with back pain of at least 3 months in duration were applied, as well as the von Korff score to assess pain intensity (visual analogue scale, VAS; 0 = no pain, 10 = worst possible pain) and pain characteristics, the Hannover Functional Ability Questionnaire (FFbH-R), and if patients agreed to provide information, the short-form Patient Health Questionnaire (PHQ-D) for depression.

Results: For 717 patients, both patient and physician questionnaires were available. Mean patient age was 56 years; pain was predominantly located in the low back (87%). Median current pain intensity on the VAS was 5.0. Confirmed key signs and symptoms indicated neuropathic pain was frequent, e.g. radicular pain radiating beyond the knee towards the foot (40.0%), positive Lasegue sign (18.4%), or absent patellar reflex (17.3%). A third of all patients (33.5%) had ≥ 3 characteristic signs for neuropathic pain. Patient functionality was severely reduced (median 43.3%). There were no relevant differences in outcomes between patients using the paper/pencil method (47%) versus those preferring PDAs (53%).

Conclusion: Screening for neuropathic pain in this setting is feasible with simple questionnaires and scales on PDAs. Neuropathic pain is a major contributor to chronic back pain and a frequent component in patients seen by orthopaedists. At least one third of all patients should undergo additional diagnostic measures to confirm the cause of neuropathic pain.     

Development and testing of a neuropathic pain screening questionnaire: ID Pain

ABSTRACT

Objective: To develop a patient-completed screening tool to help differentiate nociceptive and neuropathic pain.

Research design and methods: A multicenter study was performed for item reduction (initial 89-item questionnaire) and model building. Patients (N = 586) with non-headache chronic pain completed the questionnaire and were referred to pain specialists for diagnosis. Factor and regression analyses were used to derive a final, 6-item questionnaire – ID Pain. A second multicenter study evaluated reliability and validity. Patients (N = 308) treated by pain specialists completed ID Pain and validation measures.

Main outcome measures: Sensitivity and specificity were assessed using receiver operating characteristic curves and the concordance c index. Reliability was assessed using a κ statistic and intraclass correlation coefficient.

Results: Final 6 items were: did the pain feel: (1) like pins and needles? (2) hot/burning? (3) numb? (4) like electrical shocks? (5) is the pain made worse with the touch of clothing or bed sheets? (6) is the pain limited to your joints? ‘Yes’ answers to questions 1–5 were scored as 1, while a ‘yes’ answer to question 6 was scored as –1. ‘No’ answers were scored as 0. Higher scores (–1 to 5) suggested a neuropathic component. The questionnaire accurately predicted diagnoses of neuropathic pain made by pain specialists. The concordance c indices in the studies were 0.73 and 0.69. The ICC was 0.742; the κ statistic ranged from 0.742 to 0.527.

Conclusions: ID Pain appeared to accurately indicate the presence of a neuropathic component of pain. As a brief, self-administered screening tool, it could be useful in primary care settings.     

Treatment for chronic low back pain: the focus should change to multimodal management that reflects the underlying pain mechanisms

Chronic low back pain: Chronic pain is the most common cause for people to utilize healthcare resources and has a considerable impact upon patients’ lives. The most prevalent chronic pain condition is chronic low back pain (CLBP). CLBP may be nociceptive or neuropathic, or may incorporate both components. The presence of a neuropathic component is associated with more intense pain of longer duration, and a higher prevalence of co-morbidities. However, many physicians’ knowledge of chronic pain mechanisms is currently limited and there are no universally accepted treatment guidelines, so the condition is not particularly well managed.

Diagnosis: Diagnosis should begin with a focused medical history and physical examination, to exclude serious spinal pathology that may require evaluation by an appropriate specialist. Most patients have non-specific CLBP, which cannot be attributed to a particular cause. It is important to try and establish whether a neuropathic component is present, by combining the findings of physical and neurological examinations with the patient's history. This may prove difficult, however, even when using screening instruments.

Multimodal management: The multifactorial nature of CLBP indicates that the most logical treatment approach is multimodal: i.e. integrated multidisciplinary therapy with co-ordinated somatic and psychotherapeutic elements. As both nociceptive and neuropathic components may be present, combining analgesic agents with different mechanisms of action is a rational treatment modality. Individually tailored combination therapy can improve analgesia whilst reducing the doses of constituent agents, thereby lessening the incidence of side effects.

Conclusions: This paper outlines the development of CLBP and the underlying mechanisms involved, as well as providing information on diagnosis and the use of a wide range of pharmaceutical agents in managing the condition (including NSAIDs, COX-2 inhibitors, tricyclic antidepressants, opioids and anticonvulsants), supplemented by appropriate non-pharmacological measures such as exercise programs, manual therapies, behavioral therapies, interventional pain management and traction. Surgery may be appropriate in carefully selected patients.     

Prediction of therapeutic response to pregabalin in subjects with neuropathic pain

Objective: To evaluate four models based on potential predictors for achieving a response to pregabalin treatment for neuropathic pain (NeP).

Methods: In total, 46 pain studies were screened, of which 27 NeP studies met the criteria for inclusion in this analysis. Data were pooled from these 27 placebo-controlled randomized trials to assess if baseline characteristics (including mean pain and pain-related sleep interference [PRSI] scores), early clinical response during weeks 1–3 of treatment (change from baseline in pain and PRSI scores), and presence of treatment-emergent adverse events (AEs) were predictive of therapeutic response. Therapeutic response was defined as a ≥30% reduction from baseline in either pain and/or PRSI scores at week 5 with supplemental analyses to predict pain outcomes at weeks 8 and 12. Predictors of Patient Global Impression of Change (PGIC) were also evaluated. Four models were assessed: Random Forest, Logistic Regression, Naïve Bayes, and Partial Least Squares.

Results: The number of pregabalin-treated subjects in the training/test datasets, respectively, were 2818/1407 (30% pain analysis), 2812/1405 (30% sleep analysis), and 2693/1345 (PGIC analysis). All four models demonstrated consistent results, and the most important predictors of treatment outcomes at week 5 and pain outcomes at weeks 8 and 12 were the reduction in pain score and sleep score in the first 1–3 weeks. The presence or absence of the most common AEs in the first 1–3 weeks was not correlated with any treatment outcome.

Conclusions: Subjects with an early response to pregabalin are more likely to experience an end-of-treatment response.     

加巴喷丁与阿米替林联合治疗神经病理性疼痛

目的采用加巴喷丁联合阿米替林治疗神经病理性疼痛,观察其疗效及安全性。方法 72例神经病理性疼痛患者给予加巴喷丁及阿米替林治疗4周,采用VAS评分评估患者疗效,并观察不良反应。结果加巴喷丁及阿米替林治疗后VAS评分明显下降,P〈0.05。对各组神经病理性疼痛的治愈率均在65%以上,同时严重不良反应发生率低（为2.8%）。结论加巴喷丁联合阿米替林治疗神经病理性疼痛安全有效。     

Lithium attenuates pain-related behavior in a rat model of neuropathic pain: possible involvement of opioid system

Lithium is a major drug for bipolar disorder and mania. Recently, many studies have shown the neuroprotective effect of lithium in different models of neurodegenerative diseases. The present study was carried out to examine the effect of lithium in a rat model of neuropathic pain induced by partial sciatic nerve ligation and the possible role of opioid system in this effect. To do so, animals received acute injection of saline, lithium (5, 10 and 15 mg/kg,) and naloxone (1 mg/kg) or the combination of naloxone (1 mg/kg) with lithium (10 mg/kg) intraperitoneally on the testing days. Thermal hyperalgesia, mechanical and cold allodynia were measured on the days 3, 5, 7, 10 and 14 after surgery. Lithium decreased thermal hyperalgesia scores with dose of 5, 10 and 15 mg/kg and cold and mechanical allodynia scores with dose of 10 and 15 mg/kg, significantly. The opioid antagonist naloxone prevented the effect of lithium on thermal hyperalgesia and mechanical allodynia while it did not show any effect on the acetone-induced cold allodynia. Our results suggest that lithium can be considered as a therapeutic potential for the treatment of some aspects of neuropathic pain and that the opioid system may be involved in the lithium-induced attenuation of thermal hyperalgesia and mechanical allodynia.     

Synergy between a NR2B receptor antagonist DHQ and 3-methyl-gabapentin in mice with neuropathic pain

The synergistic effect of a selective NR2B NMDA receptor antagonist, (-)-(R)-6-{2-[4-(3-Fluorophenyl)-4-hydroxy-1-piperidinyl]-1-hydroxyethyl-3,4-dihydro-2(1H)-quinolinone (DHQ), and a alpha 2 delta ligand, 3-methyl-gabapentin (3M-GBP), was investigated in the mouse partial sciatic nerve model. The interaction was observed after administration of DHQ and 3M-GBP combination at fixed dose ratios of 1:10 and 1:30 and the dose-response curves shifted approximately 13- and 17-fold leftward, respectively, from the theoretical additive values. However, a fixed dose ratio of 1:50 resulted only in an additive effect. These results indicate the synergistic interaction between DHQ and 3M-GBP in this animal model of neuropathic pain.     

Reversal of neuropathic pain by alpha-hydroxyphenylamide: a novel sodium channel antagonist

Sodium (Na) channel blockers are known to possess antihyperalgesic properties. We have designed and synthesized a novel Na channel antagonist, alpha-hydroxyphenylamide, and determined its ability to inhibit both TTX-sensitive (TTX-s) and TTX-resistant (TTX-r) Na currents from small dorsal root ganglion (DRG) neurons. alpha-Hydroxyphenylamide tonically inhibited both TTX-s and TTX-r Na currents yielding an IC(50) of 8.2+/-2.2 microM (n=7) and 28.9+/-1.8 microM (n=8), respectively. In comparison, phenytoin was less potent inhibiting TTX-s and TTX-r currents by 26.2+/-4.0% (n=8) and 25.5+/-2.0%, respectively, at 100 microM. alpha-Hydroxyphenylamide (10 microM) also shifted equilibrium gating parameters of TTX-s Na channels to greater hyperpolarized potentials, slowed recovery from inactivation, accelerated the development of inactivation and exhibited use-dependent block. In the chronic constriction injury (CCI) rat model of neuropathic pain, intraperitoneal administration of alpha-hydroxyphenylamide attenuated the hyperalgesia by 53% at 100mg/kg, without affecting motor coordination in the Rotorod test. By contrast, the reduction in pain behavior produced by phenytoin (73%; 100mg/kg) was associated with significant motor impairment. In summary, we report that alpha-hydroxyphenylamide, a sodium channel antagonist, exhibits antihyperalgesic properties in a rat model of neuropathic pain, with favorable sedative and ataxic side effects compared with phenytoin.     

Chronic administration of amitriptyline and caffeine in a rat model of neuropathic pain: multiple interactions

This study was designed to determine (1) whether chronic amitriptyline administration was effective in alleviating symptoms of neuropathic pain in a rat model of spinal nerve injury, and (2) whether the effect of amitriptyline involved manipulation of endogenous adenosine, by determining the effect of caffeine, a non-selective adenosine A₁ and A₂ receptor antagonist, on its actions. Nerve injury was produced by unilateral spinal nerve ligation of the fifth and sixth lumbar nerves distal to the dorsal root ganglion, and this resulted in stimulus-evoked thermal hyperalgesia and static tactile mechanical allodynia. Animals received pre- and post-surgical intraperitoneal doses of amitriptyline (10 mg/kg) and caffeine (7.5 mg/kg), alone or in combination, and following surgery, were administered amitriptyline (15–18 mg/kg/day) and caffeine (6–8 mg/kg/day), alone or in combination, in the drinking water. Rats were tested for thermal reaction latencies and static tactile thresholds at 7, 14 and 21 days following surgery. In the paw ipsilateral to the nerve ligation, chronic amitriptyline administration consistently decreased the thermal hyperalgesia produced by spinal nerve ligation over a 3-week period, and this effect was blocked by concomitant caffeine administration at all time intervals. In the contralateral paw, thermal withdrawal latencies were more variable, with the most reproducible finding being a reduction in thermal thresholds in the amitriptyline–caffeine combination group. There was no effect by either drug or the drug combination on the static tactile allodynia produced by spinal nerve ligation in the ipsilateral paw. However, chronic amitriptyline administration induced a tactile hyperaesthesia in the contralateral paw at all time intervals, and this effect was exacerbated by concomitant chronic caffeine administration. The results of this study indicate that chronic administration of amitriptyline is effective in alleviating thermal hyperalgesia, but not static tactile allodynia, in the hindpaw ipsilateral to nerve injury, and the block of this effect by caffeine suggests that this effect is partially achieved through manipulation of endogenous adenosine systems. Additionally, chronic amitriptyline administration induces contralateral hyperaesthetic responses that are augmented by caffeine. Both the symptom-specific effect, and adenosine involvement in amitriptyline action may be important considerations governing its use in neuropathic pain.     

Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial

ABSTRACT

Objective: This prospective, randomized, open-label, multicenter, community-based study was conducted to compare cyclobenzaprine 5?mg three times daily (TID) orally (CYC5) given for 7 days as monotherapy or in combination with ibuprofen 400?mg TID (CYC5/IBU400) or 800?mg TID (CYC5/IBU800) in adults with acute neck or back pain with muscle spasm.

Study design: Eligible patients were 18–65 years old, had cervical or thoracolumbar pain and spasm for ≤ 14 days, and, aside from the prescribed study medications, discontinued treatment with all analgesics, anti-inflammatory agents, and skeletal muscle relaxants during the study period. Randomization was 1:1:1 to the three treatment groups. Treatment outcome was assessed after 3 and 7 days of therapy using five patient-rated scales: spasm, pain, patient global impression of change (PGIC), medication helpfulness, and Oswestry Disability Index (ODI).

Results: A total of 867 patients provided postbaseline data and were included in the intent-to-treat population (CYC5, n = 288; CYC5/IBU400, n = 286; CYC5/IBU800, n = 293). All three treatment groups demonstrated significant improvements from baseline in PGIC, spasm, pain, ODI, and medication helpfulness (?p < 0.001 for all comparisons) after 3 and 7 days of therapy. There were no significant differences in mean PGIC among groups after 3 days of therapy (?p = 0.65 for treatment effect) or after 7 days of therapy (primary endpoint; p = 0.41). A PGIC responder analysis of changes from baseline showed that 88% and 93% of patients reported at least mild improvement after 3 and 7 days of therapy, respectively. All three treatments were well tolerated, with no significant differences between treatments regarding the number of adverse events (AEs) reported or number of patients reporting AEs. The most common AEs in all groups were fatigue, somnolence, dizziness, sedation, and nausea. Limitations of this study include an unblinded design and possible introduction of bias into efficacy and safety results by use of a voluntary telephone reporting system.

Conclusions: This randomized, community-based clinical trial demonstrated that combination therapy with cyclobenzaprine 5?mg TID plus ibuprofen was not superior to cyclobenzaprine 5?mg TID alone in adult patients with acute neck and back pain with muscle spasm. All treatments were well tolerated.     

HYP-1, a novel diamide compound, relieves inflammatory and neuropathic pain in rats

In the present study, we investigated whether a novel compound, 2-(2-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-2-oxoethylamino)-N-(3,4,5-trimethoxybenzyl)acetamide (HYP-1), is capable of binding to voltage-gated sodium channels (VGSCs) and evaluated both its inhibitory effect on Na⁺ currents of the rat dorsal root ganglia (DRG) sensory neuron and its in vivo analgesic activity using rat models of inflammatory and neuropathic pain. HYP-1 showed not only high affinity for rat sodium channel (site 2), but also potent inhibitory activity against the TTX-R Na⁺ currents of the rat DRG sensory neuron. HYP-1 co-injected with formalin (5%, 50 μl) under the plantar surface of rat hind paw dose-dependently reduced spontaneous pain behaviors during both the early and late phases. This result was confirmed by c-Fos immunofluorescence in the L4-5 spinal segments. A large number of c-Fos-positive neurons were observed in rat injected with a mixture of formalin and vehicle, but not in rat treated with a mixture of formalin and HYP-1. In addition, the effectiveness of HYP-1 (6 and 60 mg/kg, i.p.) in suppression of neuropathic pain, such as mechanical, cold and warm allodynia, induced by rat tail nerve injury was investigated. HYP-1 showed limited selectivity over hERG, N-type and T-type channels. Our present results indicate that HYP-1, as a VGSC blocker, has potential analgesic activities against nociceptive, inflammatory and neuropathic pain.     

Acute and subchronic effects of amitriptyline on processing capacity in neuropathic pain patients using visual event-related potentials: preliminary findings

Rationale Little is known about the effects of low doses of amitriptyline, prescribed in the treatment of neuropathic pain, on attentional processing capacity. Objectives Changes due to amitriptyline treatment on attentional processing capacity were investigated on behavioral measures and event-related brain potentials (ERPs) in six patients with neuropathic pain. Materials and methods Patients were treated for 15 consecutive days with 25 mg nocturnally administered amitriptyline or placebo in a double-blind crossover randomized design. Measurements were carried out on day 1 and day 15 of each treatment period. An attentional capacity probe task was used in which the difficulty level was manipulated, resulting in an easy and a hard condition, while task-irrelevant visual probes were presented. During task performance, ERPs were measured from the midline electrodes Fz, Cz, Pz, and Oz. Results Amitriptyline increased reaction times (RTs) after acute but not after subchronic administration. ERP analyses showed that P3 amplitudes to the task stimuli were not affected by amitriptyline in either treatment phase. Moreover, P3 amplitudes to the probes were increased in the easy compared to the hard task condition after subchronic amitriptyline treatment, indicating beneficial effects of repeated amitriptyline administration. In contrast, acute amitriptyline administration did reduce an earlier visual evoked potential, N1, preceding the P3 component. Conclusions The results suggest that amitriptyline, even at low dosages of 25 mg, affects performance after acute administration in chronic neuropathic pain patients. After 2 weeks of treatment, performance appears to be unaffected. No deficits in processing capacity due to amitriptyline treatment were found.     

Intradermal capsaicin as a neuropathic pain model in patients with unilateral sciatica

AIM

This study compared the responses between patients with unilateral sciatica and pain-free volunteers following administration of intradermal capsaicin.

METHODS

Fourteen patients with unilateral sciatica and 12 pain-free volunteers received one injection per hour over 4 h of 1 µg and 10 µg capsaicin, into each calf. For each dose, spontaneous pain (10 cm VAS), area of flare (cm²) and the sum of allodynia and hyperalgesia radii across eight axes (cm) were recorded pre-injection and at 5, 15, 30, 45 and 60 min post injection.

RESULTS

Sciatica subjects experienced higher spontaneous pain and hyperalgesia responses in both legs compared with pain-free volunteers. The largest mean difference in spontaneous pain was 2.8 cm (95% CI 1.6, 3.9) at 5 min in the unaffected leg following 10 µg. The largest mean difference in hyperalgesia was 19.7 cm (95% CI 12.4, 27.0) at 60 min in the unaffected leg following 10 µg. Allodynia was greater in patients than in controls with the largest mean difference of 2.9 cm (95% CI 1, 4.8) at 5 min following 10 µg in the affected leg. Allodynia was also higher in the affected leg compared with the unaffected leg in sciatica patients with the highest mean difference of 3.0 cm (95% CI 1.2, 4.7) at 5 min following 10 µg.

CONCLUSIONS

The responses to intradermal capsaicin are quantitatively and qualitatively different in unilateral sciatica patients compared with pain-free controls.     

Ambroxol, a Nav1.8-preferring Na(+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain

Neuropathic pain affects many patients, and treatment today is far from being perfect. Nav1.8 Na⁺ channels, which are expressed by small fibre sensory neurons, are promising targets for novel analgesics. Na⁺ channel blockers used today, however, show only limited selectivity for this channel subtype, and can cause dose-limiting side effects. Recently, the secretolytic ambroxol was found to preferentially inhibit Nav1.8 channels. We used this compound as a tool to investigate whether a Nav1.8-preferring blocker can suppress symptoms of chronic, neuropathic and inflammatory pain in animal models. The drug was tested in the formalin paw model, two models of mononeuropathy, and a model of monoarthritis in rats. Ambroxol's effects were compared with those of gabapentin. Ambroxol at a dose of 1 g/kg had to be administered to rats to achieve the plasma levels that are reached in clinical use (for the treatment of infant and acute respiratory distress syndrome). Ambroxol (1 g/kg) was only weakly effective in models for acute pain, but effectively reduced pain symptoms in all other models; in some cases it completely reversed pain behaviour. In most cases the effects were more pronounced than those of gabapentin (at 100 mg/kg). These data show that a Nav1.8-preferring Na⁺ channel blocker can effectively suppress pain symptoms in a variety of models for chronic, neuropathic and inflammatory pain at plasma levels, which can be achieved in the clinic.