Long-term comparison between blind and ultrasound-guided corticoid injections in Morton neuroma.

OBJECTIVES: This work compares the effectiveness of blind versus ultrasound (US)-guided injections for Morton neuroma (MN) up to 3 years of follow-up. METHODS: This is an evaluator-blinded randomised trial in which 33 patients with MN were injected by an experienced orthopaedic surgeon based on anatomical landmarks (blind injection, group 1) and 38 patients were injected by an experienced musculoskeletal radiologist under US guidance (group 2). Patients were assessed using the visual analogue scale and the Manchester Foot Pain and Disability index (MFPDI). Injections consisted of 1 ml of 2% mepivacaine and 40 mg triamcinolone acetonide in each web space with MN. Up to 4 injections were allowed during the first 3 months of follow-up. Follow-up was performed by phone calls and/or scheduled consultations at 15 days, 1 month, 45 days, 2 months, 3 months, 6 months and 1, 2 and 3 years. Statistical analysis was performed using unpaired Student's t tests. RESULTS: No differences in age or clinical measures were found at presentation between group 1 (VAS, 8.5 ± 0.2; MFPDI, 40.9 ± 1.1) and group 2 (VAS, 8.4 ± 0.2; MFPDI, 39.8 ± 1.2). Improvement in VAS was superior in group 2 up to 3 years of follow-up (p < 0.05). Improvement in MFPDI was superior in group 2 from 45 days to 2 years of follow-up (p < 0.05). Satisfaction with the treatment was higher in group 2 (87%) versus group 1 (59.1%) at 3 years of follow-up. CONCLUSION: Ultrasound-guided injections lead to a greater percentage of long-term improvement than blind injections in MN. KEY POINTS: • Ultrasound-guided corticosteroid injections in Morton neuroma provide long-term pain relief in more than 75% of patients. • Ultrasound-guided injections in Morton neuroma led to greater long-term pain relief and less disability than blind injections up to 3 years of follow-up. • The presence of an ipsilateral neuroma is associated with worse long-term disability score.

Multifunctional chitin-based hollow nerve conduit for peripheral nerve regeneration and neuroma inhibition.

The recoverability for peripheral nerve lesions with a long segment defect is much challenging. Conventional methods for sciatic nerve repair excepted for autografts are bridged with nerve guidance conduit (NGC). Herein, the chitin-based NGC (ChT NGC) is firstly reported by facile dissolution, molding and regeneration process, performed excellent nerve regeneration and neuroma inhibition after deposited with anti-inflammatory polydopamine (ChT-PDA NGC). In 10 mm sciatic nerve defect rat model, the restorative effects of ChT-PDA NGC groups are similar to autografts. That is mainly ascribed to the high activity of Schwann cells and claimed by immunofluorescence staining and Western blot analysis. Interestingly, ChT-PDA NGC presents outstanding neuroma inhibition during the nerve regeneration as for the anti-inflammatory activity of PDA. This work provides a facile and novel approach to prepare hollow chitin hydrogel tube, which presents well nerve regeneration and neuroma inhibition, improving the potential high-value application of chitin in biomedical fields.

Efficacy of a Single Corticosteroid Injection for Morton's Neuroma in Adults: A Systematic Review.

BACKGROUND: Morton's neuroma is a common condition that routinely presents in podiatric practice. The aim of this study was to systematically synthesize the evidence relating to the effectiveness of a corticosteroid injection for Morton's neuroma. METHODS: Studies with a publication date of 1960 or later were eligible, and searches were performed within the Turning Research Into Practice database; the Cochrane Central Register of Controlled Trials; the Cochrane Bone, Joint and Muscle Trauma Group Specialised Register; MEDLINE (Ovid); PubMed; Embase; Cumulative Index to Nursing and Allied Health Literature; and the gray literature. Study selection criteria included randomized and nonrandomized controlled trials where a single corticosteroid injection for Morton's neuroma pain was investigated. The primary outcome was Morton's neuroma pain as measured by any standard validated pain scale. RESULTS: Ten studies involving 695 participants were included. The quality of the studies was considered low and subject to bias. Of the included studies, five compared corticosteroid injection to usual care, one compared corticosteroid injection to local anesthetic alone, one compared ultrasound-guided to non-ultrasound-guided injections, three compared corticosteroid injections to surgery, one compared small to large neuromas, six assessed patient satisfaction, four measured adverse events, one studied return to work, and one examined failure of the corticosteroid injection to improve pain. Overall, these studies identified a moderate short- to medium-term benefit of corticosteroid injections on the primary outcome of pain and a low adverse event rate. CONCLUSIONS: A single corticosteroid injection appears to have a beneficial short- to medium-term effect on Morton's neuroma pain. It appears superior to usual care, but its superiority to local anaesthetic alone is questionable, and it is inferior to surgical excision. A very low adverse event rate was noted throughout the studies, indicating the intervention is safe when used for Morton's neuroma. However, the quality of the evidence is low, and these findings may change with further research.

Medium-Term Results of Corticosteroid Injections for Morton's Neuroma.

BACKGROUND: The objective of this study was to evaluate the medium-term results of corticosteroid injections for Morton's neuroma. METHODS: This was a prospective follow-up study of a previous randomized controlled trial (RCT). Forty-five neuromas in 36 patients were injected with a single corticosteroid injection either with or without ultrasound guidance. As the results of the RCT showed no difference in outcomes between techniques, the data were pooled for the purpose of this study. Questionnaires were sent out and responses were collected via mail or telephone interview. Results were available in 42 out of 45 neuromas. There was a sex split of 68% female/32% male with a mean age of 62.6 years (SD, 12 years). RESULTS: At mean follow-up of 4.8 years (SD, 0.91 years), the original corticosteroid injection remained effective in 36% (n = 16) of the patients. In these cases, the visual analog scale (VAS) pain score (P < .001) and Manchester-Oxford Foot Questionnaire Index (MOxFQ Index) (P = .001) remained significantly better than preintervention scores. The remaining cases underwent either a further injection or surgery. Fifty-five percent of the 11 neuromas that received a second injection continued to be asymptomatic in the medium term. Overall, 44% (n = 20) of the initial cohort underwent surgical excision by the medium-term follow-up. The VAS score, MOxFQ Index, and satisfaction scale score across all groups were not significantly different. CONCLUSION: Corticosteroid injections for Morton's neuroma remained effective in over a third of cases for up to almost 5 years. A positive outcome at 1 year following a corticosteroid injection was reasonably predictive of a prolonged effect from the injection. LEVEL OF EVIDENCE: Level II, prospective comparative study.

Characterization of neuromas in peripheral nerves and their effects on heterotopic bone formation.

The formation of neuromas involves expansion of the cellular components of peripheral nerves. The onset of these disorganized tumors involves activation of sensory nerves and neuroinflammation. Particularly problematic in neuroma is arborization of axons leading to extreme, neuropathic pain. The most common sites for neuroma are the ends of transected nerves following injury; however, this rodent model does not reliably result in neuroma formation. In this study, we established a rodent model of neuroma in which the sciatic nerve was loosely ligated with two chromic gut sutures. This model formed neuromas reliably (∼95%), presumably through activation of the neural inflammatory cascade. Resulting neuromas had a disorganized structure and a significant number of replicating cells. Quantification of changes in perineurial and Schwann cells showed a significant increase in these populations. Immunohistochemical analysis showed the presence of ß-tubulin 3 in the rapidly expanding nerve and a decrease in neurofilament heavy chain compared to the normal nerve, suggesting the axons forming a disorganized structure. Measurement of the permeability of the blood-nerve barrier shows that it opened almost immediately and remained open as long as 10 days. Studies using an antagonist of the ß3-adrenergic receptor (L-748,337) or cromolyn showed a significant reduction in tumor size and cell expansion as determined by flow cytometry, with an improvement in the animal's gait detected using a Catwalk system. Previous studies in our laboratory have shown that heterotopic ossification is also a result of the activation of neuroinflammation. Since heterotopic ossification and neuroma often occur together in amputees, they were induced in the same limbs of the study animals. More heterotopic bone was formed in animals with neuromas as compared to those without. These data collectively suggest that perturbation of early neuroinflammation with compounds such as L-748,337 and cromolyn may reduce formation of neuromas.

Diagnosis of multiple endocrine neoplasia type 2B and management of its ocular features.

BACKGROUND: To describe ocular and vascular findings in a patient with multiple endocrine neoplasia type 2B. MATERIALS AND METHODS: Case report of a 31-year-old male who was referred for ocular assessment following diagnosis of a carotid artery dissection and multiple vascular anomalies. RESULTS: Clinical examination revealed a marfanoid habitus, myelinated corneal nerve fibers, neuromas in the perilimbal area, conjunctival hyperemia with peripheral corneal neovascularization, and posterior blepharitis. Diagnosis of multiple endocrine neoplasia type 2B was confirmed by genetic testing of the RET proto-oncogene. Genetic screening for hereditary aortic and peripheral vasculopathies failed to reveal an underlying cause for the vascular findings. We noted improvement of the ocular surface disease with topical corticosteroids and oral tetracyclines. CONCLUSIONS: Ophthalmologists play a vital role in recognizing this rare but lethal malignancy. We report on a patient with apart from characteristic ocular findings also staphylococcal hypersensitivity and widespread systemic vasculopathy.

Ultrasound-Guided Foot and Ankle Procedures.

This article reviews commonly performed injections about the foot and ankle region. Although not exhaustive in its description of available techniques, general approaches to these procedures are applicable to any injection about the foot and ankle. As much as possible, the procedures described are based on commonly used or published techniques. An in-depth knowledge of the regional anatomy and understanding of different approaches when performing ultrasonography-guided procedures allows clinicians to adapt to any clinical scenario.

Ultrasound-Guided Peripheral Nerve Procedures.

Ultrasound guidance allows real-time visualization of the needle in peripheral nerve procedures, improving accuracy and safety. Sonographic visualization of the peripheral nerve and surrounding anatomy can provide valuable information for diagnostic purposes and procedure enhancement. Common procedures discussed are the suprascapular nerve at the suprascapular notch, deep branch of the radial nerve at the supinator, median nerve at the pronator teres and carpal tunnel, lateral cutaneous nerve of the thigh, superficial fibular nerve at the leg, tibial nerve at the ankle, and interdigital neuroma. For each procedure, the indications, relevant anatomy, preprocedural scanning technique, and injection procedure itself are detailed.

Corticosteroid injection for Morton's neuroma with or without ultrasound guidance: a randomised controlled trial.

AIMS: The objective of this double-blind randomised controlled trial was to assess whether ultrasound guidance improved the efficacy of corticosteroid injections for Morton's neuroma (MN). PATIENTS AND METHODS: In all, 50 feet (40 patients) were recruited for this study but five feet were excluded due to the patients declining further participation. The mean age of the remaining 36 patients (45 feet) was 57.8 years (standard deviation (sd) 12.9) with a female preponderance (33F:12M). All patients were followed-up for 12 months. Treatment was randomised to an ultrasound guided (Group A) or non-ultrasound guided (Group B) injection of 40 mg triamcinolone acetonide and 2 ml 1% lignocaine, following ultrasound confirmation of the diagnosis. RESULTS: The mean visual analogue score for pain improved significantly in both groups (Group A - from 64 mm, sd 25 mm to 29 mm, sd 27; Group B - from 69 mm, sd 23 mm to 37 mm, sd 25) with no statistical difference between them at all time-points. The failure rate within 12 months of treatment was 11/23 (48%) and 12/22 (55%) in Groups A and B, respectively (p = 0.458). The improvement in Manchester Oxford Foot Questionnaire Index and patient satisfaction favoured Group A in the short-term (three months) that almost reached statistical significance (p = 0.059 and 0.066 respectively). However, this difference was not observed beyond three months. CONCLUSION: This study has shown that ultrasound guidance did not demonstrably improve the efficacy of corticosteroid injections in patients with MN. TAKE HOME MESSAGE: In the presence of a clear diagnosis of MN, a trained clinician who understands the forefoot anatomy may perform an injection without ultrasound guidance with good and safe results.

Tibioperoneal Short Circuiting for Stump Neuroma Pain in Amputees: Revival of an Old Technique.

BACKGROUND: Stump neuroma pain in amputees can be quite challenging. Surgical treatment may be largely subdivided into neuromodulative and non-neuromodulative methods. The latter includes neurocapsis, insertion of nerve stump into the bone marrow, centro-central short circuit (CCSC), and coverage with vascularized soft tissue flaps. CCSC was shown to be extremely effective in alleviation of pain. Reports on CCSC for the treatment of stump neuroma pain have disappeared from the literature, with a shift toward neuromodulation for the treatment of pain irrespective of etiology. METHODS: We observed 8 lower limb amputees undergoing CCSC of the sciatic nerve during a follow-up of 12 years. All had the same stump neuroma pain rendering them unable to wear their prostheses. The sciatic nerve was explored at the midthigh area, much proximal to the amputation site, and a short circuit was established between the tibial and peroneal parts of the nerve. Assessment was by means of pain quantification as per the quadruple visual analogue scale, medication intake, and ability to use prostheses. RESULTS: The median worst quadruple visual analogue scale before surgery was 8.0. After surgery it decreased to 2.5 (P = 0.00094). Medication intake was reduced from regular intake of a combination of opioids, nonsteroidal anti-inflammatory drugs, tricyclic antidepressants, and pregabalin in all patients to irregular intake of nonsteroidal anti-inflammatory drug alone in 3 of 8 patients. All patients were able to wear their limb prosthesis since surgery. CONCLUSIONS: CCSC is a simple, effective, and long-lasting method to treat painful stump neuromas in amputees. It should be strongly considered in deserving cases before resorting to neuromodulative methods.

Effects of alcohol injection in rat sciatic nerve as a model for Morton's neuroma treatment.

BACKGROUND: Previous studies have shown that the injection of dehydrated alcohol has been successful for the treatment of Morton's neuroma in the foot. In this study, we determined the cellular effect of injection of alcohol into and around the sciatic nerve of rats and measured the extent of cell necrosis and/or any associated histologic or inflammatory changes. METHODS: Twenty-two male (~375 g) Wistar rats were randomized into 2 groups each receiving alcohol injections into or around the sciatic nerve after nerve exposure under sterile technique. Group 1 rats were injected with a 0.5 ml solution of 0.5% Marcaine in the left sciatic nerve as a control group. In the right sciatic nerve a 0.5 ml solution of 4% ethanol with 0.5% Marcaine was injected. Group 2 rats received 0.5 ml of 20% ethanol with 0.5% Marcaine injected into the left sciatic nerve and 0.5 ml of 30% ethanol with 0.5% Marcaine injected into the right sciatic nerve. In each group, the rats were placed in 3 subgroups: intraneural, perineural, perimuscular injections. All rats were sacrificed and tissue harvested for histologic evaluation at day 10 post injection. RESULTS: No evidence of alcohol-associated cell necrosis, apoptosis, or apparent inflammation was observed in histologic specimens of any injected nerves, perineural tissue, or muscles in controls or experimental groups regardless of concentration of ethanol injected on day 10. CONCLUSION: We concluded that alcohol injection (≤30% ethanol) into and/or around the sciatic nerve or the adjacent muscle of rats has no histologic evidence of necrosis or inflammation to the nerve or surrounding tissue. There was no observable histological change in apoptosis, or cell number, in response to the alcohol injection. CLINICAL RELEVANCE: The lack of any measureable changes in nerve or adjacent muscle histology with ethanol injection into the rat sciatic nerve (and surrounding tissues) raises questions about the efficacy of using ethanol injections in the treatment of Morton's neuroma in human clinical practice.

Ultrasound-guided steroid injection in the treatment of stump neuroma: pilot study.

BACKGROUND: Stump neuroma is a major cause of postamputation pain. Ultrasound is a practical way of imaging stump neuromas and can be employed for guiding therapeutic injections. OBJECTIVE: The aim of this pilot study was to investigate the effectiveness of ultrasound-guided steroid injection in the treatment of stump neuroma. METHODS: The amputee patients with stump neuroma who underwent a single ultrasound guided steroid injection in amputee rehabilitation unit of our hospital were reviewed. The pain logs employing a 11-point pain scale for each evaluation time (before the procedure, one day, one week, 2 weeks, 4 weeks, 6 weeks after procedure) and a subsequent phone call approximately six months after procedure were used as the source of information in the study. Mean changes in pain levels (pain in rest and pain with prosthesis) over time were evaluated. The patients that had 50% decrease in pain scores were regarded as having treated successfully. Time after amputation and duration of pain symptom were compared between successfully (Group A) and unsuccessfully (Group B) treated patients. RESULTS: All patients (mean age, 29.7 ± 5.5 year) in the study were male (n=14). 12 patients were transtibial amputee (85.7%) and 2 patients were transfemoral amputee (14.3%). Both mean pain scores improved significantly in repeated measures (pain in rest F=25.35, p< 0.01; pain with prosthesis F=81,45, p <0,01). A total of 7 patients (50%) were regarded as having treated successfully. Time after amputation and duration of pain symptom were significantly longer in Group B. (p< 0.05, Group A: 16.8 ± 14.3 months after amputation, 3.5 ± 4.1 months pain duration; Group B: 80.2 ± 74.2 months after amputation, 52.8 ± 57.6 months pain duration). CONCLUSIONS: Steroid injection may have positive effect in the treatment of postamputation neuroma. The patients with shorter pain and amputation duration may respond well to the injection.

A pain model with a neuropathic somatosensory lesion: Morton neuroma.

A randomized, double-blind, three-period cross-over study was performed to characterize the sensory phenotype and pain demographics in patients with Morton neuroma (n=27) and to explore the effects of local administration (2mL) of placebo and lidocaine (1 and 10mg/mL) around the neuroma. Using the pain quality assessment scale (PQAS), the highest rating was seen for unpleasant pain and intensity of deep pain and the lowest for sensitive skin. Ongoing pain was reported in 32% of patients. Patients reported mild to moderate average pain, and that pain had interfered with sleep only marginally. Quantitative sensory testing (QST) measurements in the innervation territory showed hypophenomena or hyperphenomena in all patients, indicating that all had neuropathy. There was no particular QST modality that appeared to be specifically affected. Even the high-dose lidocaine resulted in limited effects on nerve-impulse conduction as judged by the effect on QST variables. However, both doses of lidocaine significantly reduced pain after step-ups, compared to placebo, indicating that lidocaine in this setting affected predominantly impulse generation and not impulse conduction. Following placebo treatment, pain after step-ups was similar in patients with and without hyperalgesia, indicating that the presence of hyperalgesia does not affect the pain intensity evoked by step-ups or walking. This pain model in patients with Morton neuroma allows investigation of drugs in a cross-over design and provides an opportunity to explore drug effects on both pain and QST variables. Commonly, neuromas are surgically removed and can be characterized in depth in vitro, thereby allowing close links to be established between pathophysiology and drug effect.

Treatment of Morton neuroma with botulinum toxin A: a pilot study.

BACKGROUND AND OBJECTIVE: Morton neuroma is a common cause of metatarsalgia of neuropathic origin. Systematic reviews suggest that insufficient studies have been performed on the efficacy of the different treatments available. OnabotulinumtoxinA has shown a degree of usefulness in other conditions associated with neuropathic pain. The aim of this study was to investigate the therapeutic potential of onabotulinumtoxinA in Morton neuroma. PATIENTS AND METHODS: We present an open-label, pilot study with 17 consecutive patients with Morton neuroma and pain of more than 3 months' duration that had not responded to conservative treatment with physical measures or corticosteroid injection. Patients received one onabotulinumtoxinA injection in the area of the neuroma. The main outcome measure was the variation in the pain on walking evaluated using a visual analogue scale (VAS) before treatment and at 1 and 3 months after treatment. The secondary outcome was the change in foot function, which was assessed using the Foot Health Status Questionnaire. RESULTS: In the overall group, the mean initial VAS score on walking was 7. This mean score had fallen to 4.8 at 1 month after treatment and to 3.7 at 3 months. Twelve patients (70.6 %) reported an improvement in their pain and five patients (29.4 %) reported no change; exacerbation of the pain did not occur in any patient. Improvements were also observed in two of the dimensions of the Foot Health Status Questionnaire: foot pain, which improved from a mean of 38.88 before treatment to 57 at 3 months, and foot function, which improved from a mean of 42.27 before treatment to 59.9 at 3 months. Clinical variables including age, sex, site and size of the lesion, standing activity, weekly duration of walking, footwear, foot type and footprint had no influence on the outcome. No adverse effects were reported. CONCLUSIONS: In this pilot study, injection with onabotulinumtoxinA was shown to be of possible usefulness to relieve the pain and improve function in Morton neuroma. This finding opens the door to further clinical research.

Methylprednisolone injections for the treatment of Morton neuroma: a patient-blinded randomized trial.

BACKGROUND: Morton neuroma is a common cause of neuralgia affecting the web spaces of the toes. Corticosteroid injections are commonly administered as a first-line therapy, but the evidence for their effectiveness is weak. Our primary research aim was to determine whether corticosteroid injection is an effective treatment for Morton neuroma compared with an anesthetic injection as a placebo control. METHODS: We performed a pragmatic, patient-blinded randomized trial set within hospital orthopaedic outpatient clinics in Edinburgh, United Kingdom. One hundred and thirty-one participants with Morton neuroma (mean age, fifty-three years; 111 [85%] female) were randomized to receive either corticosteroid and anesthetic (1 mL methylprednisolone [40 mg] and 1 mL 2% lignocaine) or anesthetic alone (2 mL 1% lignocaine). An ultrasonographic image was obtained before treatment, and injections were performed with the needle placed under ultrasonographic guidance. The primary outcome was the difference in patient global assessment of foot health between the two groups at three months after injection. This was measured with use of a 100-unit visual analog scale (VAS) anchored by "best imaginable health state" and "worst imaginable health state." RESULTS: Compared with the control group, global assessment of foot health in the corticosteroid group was significantly better at three months (mean difference, 14.1 scale points [95% confidence interval, 5.5 to 22.8 points]; p = 0.002). The difference between the groups was also significant at one month. Significant and nonsignificant improvements associated with the corticosteroid injection were observed for measures of pain, function, and patient global assessment of general health at one and three months after injection. The size of the neuroma as determined by ultrasonography did not significantly influence the treatment effect. CONCLUSIONS: Corticosteroid injections for Morton neuroma can be of symptomatic benefit for at least three months.

Alcohol injection for Morton's neuroma: a five-year follow-up.

BACKGROUND: Although many treatment modalities are available for Morton's neuroma (MN), studies looking at the long-term effectiveness of most forms of treatment are scarce. The injection of MN with alcohol has gained popularity over the past 10 years with widespread media coverage. Many surgeons have anecdotally questioned the long-term effectiveness of this treatment. We reviewed a cohort of patients at an average 5-year follow-up to assess the medium-term results of alcohol injection. METHODS: We used the modified Johnson score and visual analogue scales to assess 45 of the original cohort of patients with an average follow-up of 61 months (range, 33-73 months). Any complications from the procedure were also noted. RESULTS: Our results indicated that by 5 years, 16 of 45 patients had undergone surgical treatment and a further 13 patients had return of symptoms. Only 29% (13/45) remained symptom free. The visual analog scale and modified Johnson scores showed statistically significant deterioration in patients' symptoms at 5 years following alcohol injection. CONCLUSION: Injection with alcohol sclerosant for MN has been marketed as a definitive management option comparable to surgical excision. Our investigation illustrated that although short-term results are encouraging, alcohol injection does not offer permanent resolution of symptoms for most patients and can be associated with considerable morbidity. Our investigation provides the only long-term data for alcohol injection treatment of MN. LEVEL OF EVIDENCE: Level II, prospective case series.

Effects of histamine on spontaneous neuropathic pain induced by peripheral axotomy.

The present study was designed to investigate the effects of histamine on spontaneous neuropathic pain (NP) induced by peripheral axotomy. Rats and mice were subjected to complete transection of the left sciatic and saphenous nerves to induce spontaneous NP (the neuroma model). Rats were then treated with drugs once daily for 30 days (histidine and loratadine, i.p.) or 21 days (histamine, i.c.v.). Autotomy behavior was scored daily until day 50 post-operation (PO). On days 14 to 21 PO, some rats in the control group were subjected to single-fiber recording. Autotomy behavior was also monitored daily in histidine decarboxylase (the key enzyme for histamine synthesis) knockout (HDC(-/-)) and wild-type mice for 42 days. We found that both histidine (500 mg/kg) (a precursor of histamine that increases histamine levels in the tissues) and histamine (50 µg/5 µL) significantly suppressed autotomy behavior in rats. HDC(-/-) mice lacking endogenous histamine showed higher levels of autotomy than the wild-type. In addition, the analgesic effect of histidine was not antagonized by loratadine (a peripherally-acting H1 receptor antagonist), while loratadine alone significantly suppressed autotomy. Electrophysiological recording showed that ectopic spontaneous discharges from the neuroma were blocked by systemic diphenhydramine (an H1 receptor antagonist). Our results suggest that histamine plays an important role in spontaneous NP. It is likely that histamine in the central nervous system is analgesic, while in the periphery, via H1 receptors, it is algesic. This study justifies the avoidance of a histamine-rich diet and the use of peripherally-acting H1 receptor antagonists as well as agents that improve histamine action in the central nervous system in patients with spontaneous NP.