Identifying neuropathic back and leg pain: a cross-sectional study

Low back pain is a widespread debilitating problem with a lifetime prevalence of 80%, with the underlying pain mechanism unknown in approximately 90% of cases. We used the painDETECT neuropathic pain screening questionnaire to identify likely pain mechanisms in 343 patients with low back pain with or without leg pain in southeastern England referred for physiotherapy. We related the identified possible pain mechanisms nociceptive, unclear, and neuropathic to standardised measures of pain severity (Numeric Rating Scale), disability (Roland Morris Low Back Pain Disability Questionnaire), anxiety and depression (Hospital Anxiety and Depression Scale), and quality of life (Short Form 36 Health Survey Questionnaire Version 2). In addition, we investigated any relationship between these possible pain mechanisms and leg pain, passive straight leg raise, and magnetic resonance imaging evidence confirming or eliminating nerve root compression. A total of 59% of participants (n = 204) reported likely nociceptive pain, 25% (n = 85) unclear, and 16% (n = 54) possible neuropathic pain. The possible neuropathic pain group reported significantly higher pain, disability, anxiety, and depression, reduced quality of life and passive straight leg raise compared to the other pain groups (P < .05). A total of 96% of participants with possible neuropathic pain reported pain radiating to the leg (76% below the knee); however, leg pain was still more common in patients with nociceptive pain, suggesting that leg pain is sensitive to, but not specific to, possible neuropathic pain. No relationship was demonstrated between possible neuropathic pain and evidence for or absence of nerve root compression on magnetic resonance imaging scans. These findings suggest possible neuropathic pain is less common in low back pain patients referred through primary care and clarifies the usefulness of clinical tests for identifying possible neuropathic pain.     

Validation of the Dutch Version of the DN4 Diagnostic Questionnaire for Neuropathic Pain

Difficulties in diagnosing neuropathic pain in routine clinical practice support the need for validated and easy‐to‐use diagnostic tools. The DN4 neuropathic pain diagnostic questionnaire aims to discriminate neuropathic pain from nociceptive pain, but needs clinical validation. A total of 269 patients with chronic pain in three pain clinics were included in the study of which 248 had analyzable data. The mean duration of pain was 4.9 years. The most frequent etiologies were posttraumatic (36%), (pseudo) radicular (14%), and mechanical back pain (12%). The mean intensity of pain at visit was 5.6 on a 0–10 scale. Hundred and ninety‐six of 248 patients had an identical pain diagnosis from both physicians: 85 had neuropathic pain, 57 had nociceptive pain, and 54 had mixed pain. Among patients with identical diagnoses of neuropathic or nociceptive pain, using a receiver operating characteristic curve analysis, the area under the curve (AUC) was 0.81 for the DN4 7‐item and 0.82 for the 10‐item version. A cutoff point of 5/10 for the full questionnaire resulted in a sensitivity of 75% and a specificity of 79%, while a cutoff point of 4/7 for the partial questionnaire resulted in a sensitivity of 74% and a specificity of 79%. The items “brushing,” “painful cold,” and “numbness” were most discriminating. The DN4 is an easy‐to‐use screening tool that is reliable for discriminating between neuropathic and nociceptive pain conditions in daily practice. Item‐specific scores provide important information in addition to the total score.     

Modelling the prevalence and cost of back pain with neuropathic components in the general population

Background: Although there is increasing knowledge of the prevalence of neuropathic pain, little has been done to isolate the cost of neuropathic pain, especially with reference to the frequent complaint of back pain. Aims: To estimate the prevalence of neuropathic components in back pain and associated costs. Methods: We used available epidemiological data to model the prevalence of neuropathic back pain in the general adult population, combining three studies: painDETECT 1, painDETECT 2, and the German back pain research network (GBPRN) study, representing a total of 21,047 subjects. The painDETECT screening questionnaire was used in the former two surveys to assess neuropathic pain components. Costing data were obtained from 1718 participants in the GBPRN survey. Results: According to our model, approximately 4% of the general adult population experienced back pain with a neuropathic component. Owing to the greater severity of neuropathic pain, its costs were found to be disproportionately high: among patients with persistent back pain, typical costs associated with a person suffering neuropathic back pain were higher than those of an average back pain patient, and as much as 67% higher than those of a patient with nociceptive back pain only. Approximately, 16% of the total costs associated with back pain were attributable to pain with a neuropathic component. Conclusions: Back pain with neuropathic components is likely to affect a relevant proportion of the general adult population and cause a disproportionately high share of back pain‐related costs.     

Prävalenz und Charakteristik neuropathischer Schmerzen bei malignen Erkrankungen

Neuropathic pain is one of the problem areas in the management of cancer pain. In a retrospective study, prevalence and characteristics of neuropathic pain in 1318 cancer patients attending a pain clinic were examined. Of the patients, 135 suffered from neuropathic, 285 from neuropathic and nociceptive, 890 from nociceptive and 8 from unknown pain conditions. Among the patients with neuropathic pain 62% rated the pain intensity as very sincere; this was so in 48% of those with nociceptive pain. Neuropathic pain was caused by direct tumour involvement (nerve compression or infiltration) in 71%, by oncological treatment (surgery, chemotherapy, radiation) in 15%, by debilitating disease (e.g. herpes zoster) in 6% and by factors unrelated to cancer or its treatment in 8% of the patients. Of 110 clinically analysed neuropathic pain conditions, 44% were neuralgic, 31% radicular, 13% sympathically maintained, and 10% caused by deafferentiation, while in 3% the nature was unknown. To evaluate the efficacy of cancer pain treatment, nocicepetive pain has to be differentiated from neuropathic pain. In addition to this, neuropathic pain has to be divided into subgroups.     

Pelvic pain and organic dysfunction in a patient with low back pain: response to distractive manipulation: a case presentation

Many patients with low back pain demonstrate pelvic symptomatology attributable to lower sacral nerve root compression. Lower sacral nerve root compression has been identified as a cause of pelvic pain and pelvic organ dysfunction. Pelvic symptomatology secondary to lower sacral nerve root compression is given. Lower sacral nerve root compression is most commonly the result of lumbosacral disc lesion. A case of low back pain accompanied with pelvic symptomatology is presented along with its response to distractive manipulation. chiropractic treatment may be an effective means of treating pelvic disorders secondary to lower sacral nerve root compression provided that the underlying disc lesion is dealt with, although further study is needed.     

Assessing neuropathic pain in patients with low back‐related leg pain: Comparing the painDETECT Questionnaire with the 2016 NeuPSIG grading system

Background

Low back‐related leg pain with nerve root involvement is conceptually regarded as a neuropathic condition. However, it is uncertain to what extent patients with this condition can be formally classified with neuropathic pain.

Method

First, we used the 2016 revision of the IASP Special Interest Group on Neuropathic Pain (NeuPSIG) grading system for neuropathic pain to grade patients suffering from low back‐related leg pain and a corresponding disc herniation with either unlikely, possible, probable or definite neuropathic pain. Examination included bedside quantitative sensory testing. Next, we used the clinical classification based on the 2016 NeuPSIG grading system as a reference standard to assess the ability of the painDETECT Questionnaire to identify patients with neuropathic pain.

Results

Of the 50 included patients, six (12%) fulfilled the clinical classification criteria for probable and 44 (88%) for definite neuropathic pain, while none were graded unlikely or possible. According to painDETECT, 23 patients (46%) were classified with unlikely neuropathic pain, 18 patients (36%) had an uncertain condition and in nine patients (18%) neuropathic pain was likely. Among the 44 patients graded as having definite neuropathic pain by the clinical classification, eight were classified as likely neuropathic pain by painDETECT, resulting in an agreement of 18%. Of these 44 patients graded with definite neuropathic pain, painDETECT classified 21 patients (48%) as unlikely and 15 (34%) as uncertain.

Conclusion

Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in patients with low back‐related leg pain.

Significance

The painDETECT Questionnaire performed poorly at detecting neuropathic pain among patients with low back‐related leg pain, compared to clinical examination based on the 2016 NeuPSIG grading system as a reference standard. Our results do not support the use of painDETECT as a screening tool to classify or grade neuropathic components in this population.     

Dorsal root ganglion stimulation for the treatment of joint pain with predominantly nociceptive characteristics: A case series

Introduction

Dorsal root ganglion stimulation (DRG-S) has recently emerged as a novel therapy in neuromodulation that demonstrated a higher rate of success than spinal cord stimulation (SCS) in a prospective, head-to-head randomized comparative trial to treat complex regional pain syndrome (CRPS) and causalgia. In contrast to SCS, DRG-S also shows promise in treating conditions that are not purely neuropathic such as axial low back pain, which has a prominent nociplastic pain component. It is not known to what extent the effectiveness of DRG-S for such indications is due to effective treatment of the neuropathic pain component versus the effects of DRG-S on mechanical pain. Although rarely studied, reporting outcomes of DRG-S to treat predominantly mechanical/nociceptive pain may help point toward expanding the utility of this therapy. Here, we present five cases of refractory mechanical pain treated with DRG-S.

Methods

A retrospective analysis of all patients who underwent a successful DRG-S trial and implant between September 2017 and September 2021 at our institute was performed. Patients who had intractable joint pain without strong evidence of neuropathic pain were included in this case series. The Budapest criteria for CRPS, the Douleur Neuropathique 4 Questions (DN4) survey, or a definable nerve injury were used to determine the presence of neuropathic pain. Baseline assessments for pain (Numeric Rating Scale [NRS]), function (Oswestry Disability Index [ODI]), quality of life (EuroQol-5 Dimension [EQ-5D]), and other applicable joint surveys were extracted from pre-trial baseline and follow-up appointments.

Results

Five patients were identified and included. Patient diagnoses consisted of refractory joint pain of the hip, knee, or ankle. Mean NRS pain scores improved by 74% from 9.2 at baseline to 2.4 at the last follow-up (mean = 28 months post-implant). From baseline to the last follow-up, mean ODI scores improved by 65% from 66 to 23 and EQ-5D scores more than doubled from an average of 0.371 to 0.797.

Conclusion

This clinical report illustrates the potential utility DRG-S has in treating pain that clinically presents as predominantly refractory mechanical joint pain without a significant neuropathic component. The physiological reasons for our observations may be that DRG-S is able to directly influence the conduction of nociceptive signaling at the DRG and within the spinal cord. Further investigations are warranted to determine if DRG-S is a potential treatment option for chronic mechanical pain.     

Chronic inflammation and compression of the dorsal root contribute to sciatica induced by the intervertebral disc herniation in rats

The pathophysiological mechanisms underlying sciatica and back pain are not well understood. In the present study, a sciatica model was developed to investigate the contributions of inflammation and compression of the dorsal root (DR). The procedure used autologous disc to apply direct pressure to the L5 DR (disc compression, DC group). For control, five additional groups were included: (1). mechanical compression of L5 DR without disc (compression, CP group); (2). epidurally placed disc without mechanical compression (disc group); (3). epidurally placed nucleus pulposus (NP) without mechanical compression (NP group); (4). epidurally placed annulus fibrosus (AF) without mechanical compression (AF group) and (5). sham group. The paw withdrawal latency to heat stimulation, paw withdrawal threshold to mechanical stimulation, body weight, and motor function were determined pre- and post-surgery. It was observed that all experimental groups with the exception of the sham group showed a progressive and prolonged mechanical hyperalgesia with the DC group having the strongest effect. Furthermore, the disc group showed a greater mechanical hyperalgesia with earlier onset in comparison with the CP group and disc, AF, and NP groups developed thermal hyperalgesia in addition to mechanical hyperalgesia following surgery. Finally, rats in all groups showed normal motor function and body weight increase. These data suggest that this model is suitable to investigate the mechanisms of sciatica and inflammation as well as mechanical compression is involved in the pathogenesis of this condition. Moreover, AF and NP may contribute similarly to the development of sciatica and back pain.     

Characterization of Fasudil in Preclinical Models of Pain

Activation of Rho kinase (ROCK) has been shown to play a role in neuronal regeneration and development of posttraumatic neuropathic pain. The ROCK inhibitor Fasudil, used clinically for the treatment of vasospasm, was used to investigate the analgesic profile of a ROCK inhibitor. Fasudil was evaluated in different preclinical models of neuropathic, osteoarthritic (OA), and inflammatory pain as well as capsaicin-induced acute pain and secondary mechanical hypersensitivity. In addition, Fasudil was tested in in vivo electrophysiology to determine the mechanism by which Fasudil produces analgesia. Fasudil at the highest dose tested (30 mg/kg) significantly attenuated mechanical allodynia in spinal-nerve ligation (SNL; 77%), chronic constriction injury (CCI; 53%), capsaicin-induced secondary mechanical hypersensitivity (63%), sodium iodoacetate-induced OA pain (88%), and capsaicin-induced acute flinching behaviors (56%). However, Fasudil (at 30 mg/kg) failed to attenuate or had only modest effects on inflammatory thermal hyperalgesia following carrageenan injection and mechanical allodynia following Complete Freund's Adjuvant (CFA) injection. Fasudil produced ED₅₀ of 10.8 mg/kg in the SNL, and 5.7 mg/kg in the OA pain models. The ED₅₀ and 95% CI could not be obtained in the other models. Furthermore, administration of Fasudil (10 mg/kg, iv) significantly reduced both spontaneous and evoked firing of wide dynamic range (WDR) neurons in SNL, but not sham rats. Finally, Fasudil significantly decreased exploratory behaviors at 30 mg/kg. These results suggest that the acute administration of a ROCK inhibitor produces efficacy in both neuropathic and nociceptive pain states at doses devoid of locomotor side effects, with specific effects on WDR neurons.     

多节段背根节慢性压迫大鼠的机械触刺激和冷刺激诱发痛行为

目的:脊椎间盘突出、椎间孔狭窄、脊髓损伤以及肿瘤造成的背根节(dorsal root ganglion,DRG)及其邻近神经根的机械性压迫可能是引起腰背痛与坐骨神经痛的重要原因.临床上多节段神经根性痛比单一神经根性痛更常见,患者表现出多节段神经根压迫和多节段椎间孔狭窄.为此,本实验观察了多节段DRG慢性压迫大鼠的痛行为.方法:实验在本室创建的大鼠背根节慢性压迫(chronic compression of DRG,CCD)模型基础上采用单侧L3-5多节段DRG慢性压迫模型,应用von Frey细丝和丙酮分别检测机械触刺激诱发痛阚值和冷刺激诱发痛反应级别及反应百分数.结果:多节段DRG慢性压迫大鼠表现明显双侧机械触刺激诱发痛和冷刺激诱发痛行为,伴随明显延迟的对侧机械触刺激和冷刺激诱发痛的镜像痛行为.组织学观察显示多节段DRG慢性压迫同侧DRG内部及其神经根有明显炎症反应.结论:机械性压迫和炎症共同作用神经根和DRG导致多节段DRG慢性压迫大鼠明显的机械触刺激诱发痛和冷刺激诱发痛行为.     

Genetic ablation of delta opioid receptors in nociceptive sensory neurons increases chronic pain and abolishes opioid analgesia

Opioid receptors are major actors in pain control and are broadly distributed throughout the nervous system. A major challenge in pain research is the identification of key opioid receptor populations within nociceptive pathways, which control physiological and pathological pain. In particular, the respective contribution of peripheral vs. central receptors remains unclear, and it has not been addressed by genetic approaches. To investigate the contribution of peripheral delta opioid receptors in pain control, we created conditional knockout mice where delta receptors are deleted specifically in peripheral Na_V1.8-positive primary nociceptive neurons. Mutant mice showed normal pain responses to acute heat and to mechanical and formalin stimuli. In contrast, mutant animals showed a remarkable increase of mechanical allodynia under both inflammatory pain induced by complete Freund adjuvant and neuropathic pain induced by partial sciatic nerve ligation. In these 2 models, heat hyperalgesia was virtually unchanged. SNC80, a delta agonist administered either systemically (complete Freund adjuvant and sciatic nerve ligation) or into a paw (sciatic nerve ligation), reduced thermal hyperalgesia and mechanical allodynia in control mice. However, these analgesic effects were absent in conditional mutant mice. In conclusion, this study reveals the existence of delta opioid receptor-mediated mechanisms, which operate at the level of Na_V1.8-positive nociceptive neurons. Delta receptors in these neurons tonically inhibit mechanical hypersensitivity in both inflammatory and neuropathic pain, and they are essential to mediate delta opioid analgesia under conditions of persistent pain. This delta receptor population represents a feasible therapeutic target to alleviate chronic pain while avoiding adverse central effects.     

Clinical presentation of low back pain and association with risk factors according to findings on magnetic resonance imaging

We hypothesised that the relative importance of physical and psychological risk factors for mechanical low back pain (LBP) might differ importantly according to whether there is underlying spinal pathology, psychological risk factors being more common in patients without demonstrable pathology. If so, epidemiological studies of LBP could benefit from tighter case definitions. To test the hypothesis, we used data from an earlier case-control study on patients with mechanical LBP who had undergone magnetic resonance imaging (MRI) of the lumbosacral spine. MRI scans were classified for the presence of high-intensity zone (HIZ), disc degeneration, disc herniation, and nerve root displacement/compression. Information about symptoms and risk factors was elicited by postal questionnaire. Logistic regression was used to assess associations of MRI abnormalities with symptoms and risk factors, which were characterised by odds ratios (ORs) and 95% confidence intervals (CIs). Among 354 patients (52% response), 306 (86.4%) had at least 1, and 63 (17.8%) had all 4 of the MRI abnormalities. Radiation of pain below the knee (280 patients) and weakness or numbness below the knee (257 patients) were both associated with nerve root deviation/compression (OR 2.5, 95% CI 1.4 to 4.5; and OR 1.8, 95% CI 1.1 to 3.1, respectively). However, we found no evidence for the hypothesised differences in risk factors between patients with and without demonstrable spinal pathology. This suggests that when researching the causes and primary prevention of mechanical LBP, there may be little value in distinguishing between cases according to the presence or absence of the more common forms of potentially underlying spinal pathology.     

Impairment of VGLUT2 but not VGLUT1 signaling reduces neuropathy‐induced hypersensitivity

Glutamate is the major excitatory neurotransmitter in the central nervous system with an important role in nociceptive processing. Storage of glutamate into vesicles is controlled by vesicular glutamate transporters (VGLUT). Null mutants for VGLUT1 and VGLUT2 were poorly viable, thus, pain‐related behavior was presently compared between heterozygote VGLUT1 and VGLUT2 mice and their respective wild‐type littermates using a test battery that included a variety of assays for thermal and mechanical acute nociception, and inflammatory and neuropathic pain syndromes. Behavioral analysis of VGLUT1 mutant mice did not show important behavioral changes in the pain conditions tested. Reduction of VGLUT2 also resulted in unaltered acute nociceptive and inflammatory‐induced pain behavior. Interestingly, VGLUT2 heterozygote mice showed an attenuation or absence of some typical neuropathic pain features (e.g., absence of mechanical and cold allodynia after spared nerve injury). Chronic constriction injury in VGLUT2 heterozygote mice showed also reduced levels of cold allodynia, but had no impact on mechanical thresholds. Together, these data suggest that VGLUT2, but not VGLUT1, plays a role in neuropathy‐induced allodynia and hypersensitivity, and might be a therapeutic target to prevent and/or treat neuropathic pain.     

Role of TNF-alpha in sensitization of nociceptive dorsal horn neurons induced by application of nucleus pulposus to L5 dorsal root ganglion in rats

Herniation of the nucleus pulposus (NP) from lumbar intervertebral discs commonly results in radiculopathic pain and paresthesia (sciatica). While traditionally considered the result of mechanical compression of the dorsal root ganglion (DRG) and/or spinal nerve root, recent studies implicate pro-inflammatory mediators released from or evoked by NP, a possibility that was presently investigated. Single-unit recordings were made from L5 wide dynamic range dorsal horn neurons in pentobarbital-anesthetized rats. Autologous NP was harvested from a coccygeal disc and placed onto the exposed L5 DRG. A control group had subcutaneous adipose tissue or saline placed similarly. To test involvement of tumor necrosis factor- (TNF-), a third group received autologous NP plus local soluble TNF- receptor type 1 (0.013 μg) which binds TNF- to prevent its action. In each group, neuronal responses to graded heat (38–50 °C) and mechanical (von Frey filaments 4–76 g) stimuli were recorded prior to and at three successive hourly intervals following each treatment. Responses to noxious heat and mechanical stimuli were significantly enhanced 1 h post-NP and remained elevated thereafter. Thermally and mechanically evoked responses were not significantly affected in control rats or those treated with NP+soluble TNF- receptor type 1. These results indicate that sensitization of nociceptive spinal neuronal responses develops quickly following exposure of the DRG to NP, and that TNF- is involved. This electrophysiological model of herniated NP may prove useful in further characterizing the role of inflammatory mediators in hyperalgesia and allodynia resulting from lumbar disc herniation.     

Lumbar extension exercises in conjunction with mechanical traction for the management of a patient with a lumbar herniated disc

ABSTRACT

Low back pain resulting from lumbar disc herniation is a common reason for referral for physical therapy. There is no evidence to support the management of lumbar disc herniation and derangement using mechanical traction combined with lumbar extension exercises. Therefore, the purpose of this case report was to describe and discuss the use of mechanical traction in conjunction with lumbar extension exercises for a patient with a lumbar herniated disc. The patient was a 49-year-old male referred to physical therapy with a medical diagnosis of a lumbar herniated disc at L5-S1 with compression of the L5 nerve root confirmed by MRI. The patient's chief complaint was pain over the left lumbosacral and central lumbar region with radiating pain into the left buttock accompanied by numbness and tingling in the left lower leg and foot. The patient was seen for a total of 14 visits. The first 5 days (2 weeks) of therapy consisted of lumbar extension exercises. For the following nine visits (over a 3-week period), mechanical traction was added as an adjunct to the extension exercises. Outcome measures included the Oswestry Disability Questionnaire, Back Pain Function Scale (BPFS), and the Numeric Pain Rating Scale (NPRS). Results from initial evaluation to discharge (Oswestry: 36% to 0%; BPFS: 33/60 to 57/60; NPRS: 7/10 to 0/10) demonstrated that the patient no longer experienced low back pain and improved in terms of functional status and pain-related disability. The patient no longer complained of numbness and tingling in the left lower extremity and the goals for the patient had been attained. The data from this case report suggests lumbar extension exercises in conjunction with mechanical traction facilitated the patient's improvement in pain and return to prior level of function.     

Central pituitary adenylate cyclase 1 receptors modulate nociceptive behaviors in both inflammatory and neuropathic pain states.

The pituitary adenylate cyclase-activating polypeptide type 1 receptor (PAC(1)-R) is a member of the 7-transmembrane domain, group 2 G-protein coupled receptor family. PAC(1)-Rs modulate neurotransmission and neurotrophic actions and have been implicated in both pronociception and antinociception. To better understand the role of PAC(1)-Rs in pain, PACAP 6-38, a PAC(1)-R antagonist, was evaluated in several inflammatory and neuropathic pain models after intrathecal (i.t.) administration. PACAP 6-38 potently reduced mechanical allodynia in a neuropathic spinal nerve ligation model (77% +/- 15% maximal effect at 12 nmol, P < .01) and was also effective in reducing thermal hyperalgesia in the carrageenan model of inflammatory pain (89% +/- 17% maximal effect at 12 nmol, P < .01). Although nociceptive responses were also attenuated with PACAP 6-38 in a dose-dependent manner in models of chronic inflammatory and persistent pain, no effects on motor performance were observed at analgesic doses. Taken together, these data demonstrate that blockade of the PAC(1)-R/PACAP complex by PACAP 6-38 can effectively attenuate thermal hyperalgesia and mechanical allodynia associated with inflammatory and neuropathic pain states. These results further emphasize that at the level of the spinal cord, PAC(1)-R activation is pronociceptive. PERSPECTIVE: This article presents the analgesic profile generated by the blockade, at the spinal cord level, of the PAC-1 receptor by a potent peptide antagonist. This comprehensive data set demonstrates that if small molecule PAC-1 receptor antagonists could be identified, they would potentially produce broad-spectrum analgesia in both inflammatory and neuropathic pain states.     

Inflammatory and neuropathic pain are rapidly suppressed by peripheral block of hyperpolarisation-activated cyclic nucleotide-gated ion channels

Previous studies have shown that hyperpolarisation-activated cyclic nucleotide-gated (HCN)–2 ion channels regulate the firing frequency of nociceptive sensory neurons and thus play a central role in both inflammatory and neuropathic pain conditions. Here we use ivabradine, a clinically approved anti-anginal agent that blocks all HCN channel isoforms approximately equally, to investigate the effect on inflammatory and neuropathic pain of HCN ion channel block. We show that ivabradine does not have major off-target effects on a sample group of Na, Ca, and K ion channels, and that it is peripherally restricted because it is a substrate for the P-glycoprotein (PgP) multidrug transporter that is expressed in the blood–brain barrier. Its effects are therefore likely to be due to an action on HCN ion channels in peripheral sensory neurons. Using patch clamp electrophysiology, we found that ivabradine was a use-dependent blocker of native HCN channels expressed in small sensory neurons. Ivabradine suppressed the action potential firing that is induced in nociceptive neurons by elevation of intracellular cAMP. In the formalin model of inflammatory pain, ivabradine reduced pain behaviour only in the second (inflammatory) phase. In nerve injury and chemotherapy models of neuropathic pain, we observed rapid and effective analgesia as effective as that with gabapentin. We conclude that both inflammatory and neuropathic pain are rapidly inhibited by blocking HCN-dependent repetitive firing in peripheral nociceptive neurons.