Are you better? A multi-centre study of patient-defined recovery from Complex Regional Pain Syndrome.

BACKGROUND: Complex Regional Pain Syndrome (CRPS) symptoms can significantly differ between patients, fluctuate over time, disappear or persist. This leads to problems in defining recovery and in evaluating the efficacy of therapeutic interventions. OBJECTIVES: To define recovery from the patients' perspective and better understand their priorities for treatment approaches. METHODS: Establishing an international consortium, we used a 2-Round Delphi-based study in eight countries across Europe and North America. Participants ≥18 years who met, or had met, Budapest clinical criteria were included. Round 1 participants completed the statement: 'I would/do consider myself recovered from CRPS if/because…' alongside demographic and health questionnaires. Data were thematically organised and represented as 62 statements, from which participants identified and ranked their recovery priorities in Round 2. RESULTS: Round 1 (N = 347, 80% female, 91% non-recovered) dominant ICF themes were: activities of daily living; bodily functions; external factors; participation and personal factors. The top five priority statements in Round 2 (N = 252) were: no longer having (1) CRPS-related pain, (2) generalised pain and discomfort, (3) restricted range of movement, (4) need for medication, (5) stiffness in the affected limb. With very few exceptions, priorities were consistent, irrespective of patient demographics/geography. Symptoms affecting daily activities were among those most frequently reported. CONCLUSIONS: Our data showed a small number of themes are of highest importance to CRPS patients' definition of recovery. Patients want their pain, movement restriction and reliance on medication to be addressed, above all other factors. These factors should therefore be foremost concerns for future treatment and rehabilitation programmes. SIGNIFICANCE: Those with longstanding CRPS may no longer meet diagnostic criteria but still be symptomatic. Defining recovery is therefore problematic in CRPS. Our study has identified patients' definition of recovery from CRPS, in order of priority, as relief from: their CRPS-related pain, generalised pain, movement restriction, reliance on medication, and stiffness.

Treatment of painful radiculopathies with capsaicin 8% cutaneous patch.

BACKGROUND AND OBJECTIVE: The treatment of neuropathic pain due to low-back (lumbosacral) radiculopathies, a common source of neuropathic pain, is challenging and often requires a multimodal therapeutic approach. The capsaicin 8% patch is the first topical analgesic licensed for peripheral neuropathic pain. To evaluate this treatment, a subset of patients with painful radiculopathy (lumbar and cervical, including ventral and dorsal rami) enrolled into the multicenter, non-interventional QUEPP study (Qutenza 2 - safety and effectiveness in peripheral neuropathic pain) was analyzed. METHODS: Of the 1044 study participants, 50 were diagnosed with painful radiculopathy as only peripheral neuropathic pain syndrome and were eligible for evaluation. Patients received a single treatment (visit 1) with follow-up visits 2-5 at weeks 1-2, 4, 8 and 12. Parameters assessed at all visits included pain intensity, neuropathy symptoms and side effects. Quality of life (SF-12) and painDETECT 1 questionnaires were completed at baseline and final visit. Data was analyzed by patch application site and duration of pain. RESULTS: Topical treatment led to a significant decrease of pain intensity between weeks 1/2 and week 12 versus baseline at the application sites representing dermatomes of ventral (N = 26) and dorsal rami (N = 13) of spinal nerves. A significant decline (p ≤ .001) of numeric pain rating scale scores was observed between weeks 1/2 following patch application and the end of observation (week 12) in the overall radiculopathy group (N = 50), and the groups with either 3 months to 2 years (N = 14) or >2 years (N = 23) duration of pain. Pain relief of at least 30% was observed in 50.0%, 71.4% and 39.1% of patients in the respective groups. Four patients experienced in total seven adverse drug reactions (application site pain or pruritus). CONCLUSION: Effective neuropathic pain relief was observed after patch application within the innervation territories of both dorsal and ventral branches of the spinal nerve. Further controlled randomized trials are indicated.

Increased prevalence of posttraumatic stress disorder in CRPS.

BACKGROUND: Although specific psychological disorders in complex regional pain syndrome (CRPS) have not been identified, studies suggest that CRPS patients may have increased rates of traumatic life events. Because these events do not always lead to apparent psychological symptoms, we systematically screened CRPS patients for posttraumatic stress disorder (PTSD) to determine if PTSD could be a risk factor for CRPS. METHODS: Consecutive CRPS patients referred to two university hospital centres (University of Erlangen, UMC Mainz) between December 2011 and April 2013 were prospectively examined using a diagnostic PTSD instrument (Post-traumatic Stress Diagnostic Scale (PDS). We also tested maladaptive coping strategies (brief-COPE inventory) and the PDS severity score as predictors for CRPS. Patients with non-CRPS extremity pain and healthy individuals were used as control groups. RESULTS: We collected data from 152 patients with CRPS, 55 control patients and 55 age- and sex-matched healthy individuals. Fifty-eight CRPS patients (38%), six non-CRPS pain patients (10%) and two healthy individuals (4%) met diagnostic criteria for PTSD. Initial PTSD symptom onset was prior to CRPS in 50 CRPS patients (86%) and during the course of CRPS in eight patients. Results of a logistic regression revealed that the PTSD severity score was associated with CRPS (p < 0.0001). Maladaptive coping strategies (p < 0.0001) were related to PTSD. CONCLUSIONS: posttraumatic stress disorder (PTSD) is more frequent in patients with CRPS than it is in the general population. SIGNIFICANCE: Research has not yet provided support for specific psychological predictors for CRPS.

[Pain - a neglected neurological issue]. / Schmerz - ein vernachlässigtes neurologisches Thema.

Chronic pain represents a great challenge; according to epidemiological data increasing numbers of patients should be expected. Based on recent advances, a better understanding of the pathophysiology of chronic pain has been achieved and neurologists have made a major contribution to this understanding. Chronic pain is accompanied by substantial maladaptive plastic alterations in both the peripheral and central nervous systems; therefore, neurological knowledge is of paramount importance for pain therapists but this contrasts with the current treatment situation of pain patients in Germany. There are basically too few departments and practices undertaking treatment, and neurologists are an exception in most pain centers. Furthermore, due to economic reasons neurological hospitals are currently experiencing a dearth of inpatients suffering from chronic pain. Diagnostic and/or treatment procedures for neurological pain entities (e.g. headaches or neuropathic pain) are insufficiently represented in the German diagnosis-related groups (DRG) reimbursement system and the obstacles for an efficient pain therapy in neurological practices are too high. Finally, there are too few academic positions for pain medicine in neurological hospitals; therefore, career opportunities for motivated young neurologists with an interest in pain are lacking. In order to address the unmet therapeutic needs of patients with chronic pain there is a high demand for (i) establishment of departments for neurological pain medicine, (ii) modification of the German DRG system and (iii) education of young neurologists with expertise in pain. Pain medicine in particular should be especially appealing to neurologists .

[Imaging techniques and pain]. / Bildgebung und Schmerz.

Over the last 15 years, functional brain imaging techniques have provided critical insights into cortical, subcortical and even spinal mechanisms involved in pain perception and pain modulation in humans. The pivotal contribution of brain imaging studies conducted in Germany have thereby been internationally acknowledged. One of the key challenges for the next decade is to shift the focus from studies in healthy volunteers to different clinical populations suffering from chronic pain to characterize CNS mechanisms, as well as neurobiological predictors and resilience factors of pain chronification. Ultimately, the knowledge gained by this work may help identify individual or syndrome-specific CNS changes as biomarkers to make therapeutic decisions.

[Capsaicin 8 % cutaneous patches for phantom limb pain. Results from everyday practice (non-interventional study)]. / Das 8 %ige Capsaicin-Pflaster bei Phantomschmerz. Ergebnisse aus dem Praxisalltag (nichtinterventionelle Studie).

BACKGROUND: Post amputation pain presents a challenge for pain physicians and is often detrimental to the patient's quality of life. PATIENTS AND METHODS: A prospective 12-week non-interventional study (NIS) was conducted in Germany to obtain data on the effectiveness and safety of capsaicin 8 % cutaneous patches from real life use in patients with peripheral neuropathic pain. For the first time in a subgroup of amputees data on post amputation pain were collected. This article presents the results for patients who suffered from phantom limb pain (PLP), stump pain (SP) and combined phantom limb/stump pain (PLP/SP). RESULTS: The analyses included 21 patients with post amputation pain (PLP: n = 10, SP: n = 4, PLP/SP: n = 7). The mean duration of pain (± standard deviation) was 12.8 ± 13.0 years for PLP, 23.1 ± 29.9 years for SP and 11.0 ± 15.8 years for PLP/SP. A single treatment with capsaicin 8 % cutaneous patches significantly reduced the average pain intensity over the observational period of 12 weeks. The mean numeric pain rating scale (NPRS) baseline score changed by - 2.4 for PLP with a standard error of the mean (SEM) of 0.4 (median: - 2.9, Q1: - 3.5, Q3: - 1.0), - 1.7 for SP (SEM: 0.8, median: - 1.1, Q1: - 2.9, Q3: - 0.5) and - 1.5 for PLP/SP (SEM: 0.6, median: - 2.0, Q1: - 2.3, Q3: 0) during weeks 1-12. The 30 % responder rates (i.e. ≥ 30 % reduction in pain, day 7/14 to week 12) were 70.0 % (PLP), 50.0 % (SP) and 28.6 % (PLP/SP). PLP and PLP/SP patients in particular, benefited from improvements in pain attacks, sleep duration and sleep quality and one patient (PLP/SP) reported an adverse drug reaction (increase of pain). Physicians rated the tolerability of the patch as very good or good in 90.5 % of patients. A poor tolerability was stated for none of the 21 amputees. Of the patients 80 % for PLP and 50 % for both SP and PLP/SP expressed the wish to receive retreatment with capsaicin 8 % patches. CONCLUSION: Capsaicin 8 % cutaneous patches seem to be effective and safe for the treatment of post amputation pain, notably in patients suffering from phantom limb pain.

[Complex regional pain syndrome: A current review]. / Komplexes regionales Schmerzsyndrom: Eine aktuelle Übersicht.

Complex regional pain syndrome (CRPS) may develop following fractures, limb trauma, or lesions of the peripheral or central nervous system. The clinical picture consists of a triad of symptoms including autonomic, sensory, and motor dysfunction. Diagnosis is based on clinical signs and symptoms according to the Budapest criteria. Therapy is based on an individual and multidisciplinary approach. Distinct methods of physical therapy and pharmacological strategies are the mainstay of therapy. Pharmacotherapy is based on individual symptoms and includes steroids, free radical scavengers, treatment of neuropathic pain, and agents interfering with bone metabolism. In some cases invasive methods may be considered.

Insula and sensory insular cortex and somatosensory control in patients with insular stroke.

BACKGROUND: In functional imaging studies, the insular cortex (IC) has been identified as an essential part of the processing of a whole spectrum of multimodal sensory input. However, there are no lesion studies including a sufficient number of patients, which would reinforce the functional imaging data obtained from healthy subjects. Such lesion studies should examine how damage to the IC affects sensory perception. We chose acute stroke patients with lesions affecting the IC in order to fill this gap. METHODS: A comprehensive sensory profiling by applying a quantitative sensory testing protocol was performed and a voxel-lesion behaviour mapping analysis in 24 patients with acute unilateral cortical damage was applied. RESULTS: Our data demonstrate that patients with lesions of the posterior IC have deficits in temperature perception, but did not show other sensory deficits such as hot or cold pain perception associated with specific lesion locations. CONCLUSION: Our data allow the conclusion that the posterior IC may represent the major region responsible for encoding warm and cold perception in the brain. To what extent focal IC lesions may also impair pain processing or induce post-stroke pain has to be addressed in future studies including more patients.

Brain correlates of short-term habituation to repetitive electrical noxious stimulation.

BACKGROUND: Habituation to repetitive noxious stimuli is a well-known phenomenon. We investigated brain correlates of habituation to pain in a transdermal electrical pain model using functional magnetic resonance imaging (fMRI). METHODS: Electrical painful stimulation with 1 Hz was applied to the volar forearm of 48 healthy subjects for 45 min. Before and after conditioning stimulation, psychophysical testing and fMRI were performed. During fMRI sessions, the subjects underwent blockwise painful electrical stimulation with a fixed percept-adapted current intensity. After fMRI 1 and fMRI 2 subjects rated the individual pain intensity of the electrical stimulus. RESULTS: Substantial habituation occurred during conditioning electrical stimulation. Accordingly, areas typically involved in pain processing showed decreased activity after conditioning stimulation. The blood oxygen level-dependent signal of the subgenual anterior cingulate gyrus, the superior parietal lobule and the supplemental motor area correlated positively with habituation. In contrast, activity in the periaqueductal grey, thalamus and insula correlated negatively. The results of the correlation analyses did not survive correction for multiple comparisons. CONCLUSIONS: With this study, we identified central components associated with habituation to repetitive painful stimuli. The results suggest that an increase in tonic inhibitory activity in cortical pain processing areas is a major mechanism contributing to habituation to phasic noxious stimuli. Moreover, areas involved in descending pain modulation were differentially modulated. This may hint at a simultaneous activation of facilitating and inhibiting nociceptive systems that are both altered in the transdermal electrical pain model.

Treatment of peripheral neuropathic pain by topical capsaicin: Impact of pre-existing pain in the QUEPP-study.

BACKGROUND: This study evaluates the impact of the duration of pre-existing peripheral neuropathic pain on the therapeutic response to the capsaicin 8% cutaneous patch. METHODS: The non-interventional QUEPP (QUTENZA - safety and effectiveness in peripheral neuropathic pain) study evaluated the effectiveness of Qutenza(TM) in 1044 non-diabetic patients with peripheral neuropathic pain, who received a single application. Follow-up visits were scheduled at weeks 1-2, 4, 8 and 12. A pre-defined co-analysis of changes in average pain intensity was performed based on the duration of pre-existing pain. RESULTS: In patients with pre-existing pain for <6 months, the mean relative change of the numeric pain rating scale score on days 7-14 to week 12 versus baseline was -36.6% [4.6 standard error of the mean (SEM); n = 105], -25.1% (1.9 SEM; n = 311) in patients with pain duration of 6 months to 2 years, -22.3% (1.6 SEM; n = 391) in patients with pain for >2-10 years, and -19.2% (2.6 SEM; n = 99) in patients with pain for >10 years. Thirty percent and 50% responder rates were 61.7% and 39.3% in patients with pre-existing pain for <6 months, 42.3% and 23.3% in patients with pain for 6 months to 2 years, 40.9% and 21.6% in patients with pain for >2-10 years, and 32.3% and 14.1% in patients with pain for >10 years. CONCLUSIONS: The highest treatment response to the capsaicin 8% cutaneous patch was observed in patients with a history of pre-existing peripheral neuropathic pain of less than 6 months, suggesting that early initiation of topical treatment might be indicated.

[Migraine - established concepts and new developments]. / Migräne - Bewährtes und aktuelle Entwicklungen.

Migraine is a very common primary headache disorder associated with intermittent attacks and great suffering. Despite extensive research efforts in the recent years, many pathophysiological aspects remain unclear. An altered cortical adaptability and the brainstem as a migraine generator are probably involved in the initiation of a (silent) cortical spreading depression and other processes that lead to neurogenic inflammation of the meninges causing the headache. Numerous studies in the last years have examined somatic, especially cerebrovascular and also psychological comorbidities. For attack therapy, CGRP antagonists have emerged as promising non-vasoconstrictive acting alternatives for triptans. However, they were so far not approved due to liver enzyme elevations in safety studies. Another new approach without vasoconstrictive action are the selective 5-HT1F agonists (especially Lasmiditan). Large placebo-controlled and triptan-controlled trials need to be awaited. For migraine prophylaxis, a comparable effect of sports and pharmacological prophylaxis using topiramate could be found. Particularly the combination of drug and non-drug therapies (such as the combination of stress management training with a beta-blocker treatment) achieves high efficacy. Also interdisciplinary, multimodal treatment approaches are important options. Two large multicentre studies have demonstrated the efficacy of botulinum toxin A as a prophylactic treatment for chronic migraine. Neuromodulative and neurostimulative procedures are promising but still experimental treatment options for patients with refractory migraine.

Prospective, non-interventional study on the tolerability and analgesic effectiveness over 12 weeks after a single application of capsaicin 8% cutaneous patch in 1044 patients with peripheral neuropathic pain: first results of the QUEPP study.

BACKGROUND: Reversible defunctionalisation of nociceptors by the TRPV1 agonist capsaicin in high concentration is an emerging new concept for the treatment of peripheral neuropathic pain. OBJECTIVES: The capsaicin 8% cutaneous patch with a long-lasting effect for up to 3 months after a single application is available in Germany by prescription since October 2010. The aim of this study was to monitor its usage and therapeutic performance in clinical practice. METHODS: Patients had a single patch application with up to 4 patches and were followed up after 7-14 days, 4, 8, and 12 weeks. Average pain intensity (NPRS-11), pain attacks, neuropathy symptoms, sleep parameters, quality of life, working capacity and concomitant neuropathic pain medication were assessed during at least two visits. RESULTS: A total of 509 females (48.8%; effectiveness population N = 1044) and 531 males (50.9%) were included; the mean age was 61.2 ± 14.4 (SD) years. Postherpetic neuralgia was the most frequent diagnosis (31.9%), followed by postsurgical neuralgia (22.8%), post-traumatic neuropathy (12.4%), polyneuropathy (14.3%), and mixed pain syndromes (16.6%). Thirty and 50% responder rates were 42.7% and 23.7%, respectively, with a mean relative reduction of pain intensity during weeks 1-12 of 24.7% (1.1 SEM) and significant improvements in pain attacks, sleep duration and sleep quality, while the consumption of opioids and antiepileptics decreased significantly. In 106 patients (10.0%; safety population n = 1063) 146 adverse drug reactions (ADRs) were reported, mainly application site reactions (erythema, pain). A total of 27 serious ADRs were documented in 17 patients (1.6%). CONCLUSIONS: Analgesic treatment of peripheral neuropathic pain with the capsaicin 8% cutaneous patch is safe and effective. LIMITATIONS: The study did not include a control group; therefore, a comparison of the results with that of therapeutic alternatives is not justified.

[Trigeminal autonomic cephalgias - new aspects and concepts]. / Trigemino-autonome Kopfschmerzen - neue Aspekte und Konzepte.

Cluster headache, paroxysmal hemicrania and SUNCT syndrome are a group of primary headaches classified as "trigeminal autonomic cephalgias" (TACs) and characterised by relatively short attacks of unilateral head pain associated with ipsilateral craniofacial autonomic manifestations. Duration of attacks is the main feature to distinguish between the three forms of TACs. Modern functional neuroimaging indicates that the hypothalamus may play a crucial role in the pathophysiology of these headaches. Therapeutic regimes consist of acute treatment as well as application of prophylactic medication. After unsuccessful application of conservative treatment options, invasive neuromodulative procedures are finally justified. These treatments should be rather of neurostimulative than of neurodestructive intentions.

[Diagnostic guidelines for complex regional pain syndrome]. / Leitfaden zur Diagnostik des Komplexen regionalen Schmerzsyndroms.

The complex regional pain syndrome, a special form of neuropathic pain, develops after a minor trauma of the distal limbs. Besides the presentation of pain disproportional to the inciting event, further plus and minus symptoms in the form of sensory, vasomotor, sudomotor-oedematous and motor-trophic changes can be found. Interindividually and intraindividually, occurrence of these symptoms differs widely and single symptoms can be lacking completely. A gold standard in diagnosing CRPS has not been found yet, diagnostics are based on the patients medical history and correlating clinical signs. The International Association for the Study of Pain (IASP) compiled and later on revised operational diagnostic criteria resulting in a satisfactory sensitivity and specificity for both research and clinical needs. Additionally, diagnostic tools can support the clinical suspicion - reasonable tests are conventional X-ray examination comparing sides, magnetic resonance imaging and a 3-phase bone scintigraphy. Moreover, electrophysiological examinations can prove a nerve lesion and differentiate between CRPS type I and II. A temperature difference can be detected via infrared thermography. Furthermore, quantitative sensory testing can verify the magnitude of the sensory disturbance and can be beneficial to objectify therapeutic effects. Use of these diagnostic tools, even after achievement of normal findings, cannot exclude a CRPS and the decision for therapeutic initiation should not be influenced thereby.

Cerebral mechanisms of experimental hyperalgesia in fibromyalgia.

The present study examined the hyperresponsiveness of the central nervous system in patients with fibromyalgia syndrome (FMS) related to mechanical hyperalgesia. The goals were to differentiate between increased pain ratings and hyperalgesia related either to peripheral or to central sensitization and to correlate with cerebral activation pattern. Seventeen patients and 17 healthy controls were examined, placing an experimental incision in the right volar forearm and causing tonic pain. Experimental pain, primary and secondary hyperalgesia were assessed during the time course of the experimental pain, and the changes in hyperalgesia were correlated to brain activation (functional magnetic resonance imaging). Patients with FMS experienced the experimental pain during the time course as more painful than healthy controls (F(score) = 3.93, p(score) = 0.008). While they did not present a different course of primary hyperalgesia (F(score) = 1.01, p(score) = 0.40), they did show greater secondary hyperalgesia (F(score) = 5.45, p(score) = 0.004). In patients with FMS, the cerebral pattern corresponding to secondary hyperalgesia was altered. The activity in the dorsolateral prefrontal cortex was inversely correlated with secondary hyperalgesia in healthy controls (R = -0.34 p = 0.005); in patients, this correlation was disrupted (R = 0.19 p = 0.12). These findings point to an alteration of pain transmission at the central level in FMS (e.g., loss of inhibition) and might be related to changes in cerebral-midbrain-spinal mechanisms of pain inhibition.

Time perception in patients with major depressive disorder during vagus nerve stimulation.

BACKGROUND: Affective disorders may affect patients' time perception. Several studies have described time as a function of the frontal lobe. The activating eff ects of vagus nerve stimulation on the frontal lobe might also modulate time perception in patients with major depressive disorder (MDD). METHODS: Time perception was investigated in 30 patients with MDD and in 7 patients with therapy-resistant MDD. In these 7 patients, a VNS system was implanted and time perception was assessed before and during stimulation. A time estimation task in which patients were asked "How many seconds have passed?" tested time perception at 4 defined time points (34 s, 77 s, 192 s and 230 s). The differences between the estimated and actual durations were calculated and used for subsequent analysis. RESULTS: Patients with MDD and healthy controls estimated the set time points relatively accurately. A general linear model revealed a significant main eff ect of group but not of age or sex. The passing of time was perceived as significantly slower in patients undergoing VNS compared to patients with MDD at all time points (T34: t = − 4.2; df = 35; p < 0.001; T77: t = − 4.8; df = 35; p < 0.001; T192: t = − 2.0; df = 35; p = 0.059; T230 t = −2.2; df = 35; p = 0.039) as well as compared to healthy controls (at only T77: t = 4.1; df = 35; p < 0.001). There were no differences in time perception with regard to age, sex or polarity of depression (uni- or bipolar). CONCLUSIONS: VNS is capable of changing the perception of time. This discovery furthers the basic research on circadian rhythms in patients with psychiatric disorders.

Central opioidergic neurotransmission in complex regional pain syndrome.

OBJECTIVE: Complex regional pain syndrome (CRPS) is a chronic pain condition characterized by sensory, motor, and autonomic symptoms. It develops after limb trauma and may be associated with relevant psychiatric comorbidity. As there is evidence for central pathophysiology which might be related to an altered opioidergic neurotransmission, we investigated the cerebral opioid receptor status under resting conditions in this patient population. METHODS: In this case-control study, 10 patients with CRPS and 10 age- and gender-matched healthy subjects underwent a PET scan using the subtype-nonselective opioidergic radioligand [(18)F]fluoroethyl-diprenorphine. As a surrogate for regional cerebral opioid receptor availability, the opioid receptor binding potential (OR-BP) was assessed by means of the modified Logan plot with reference region input for categorical group comparison and correlation with clinical data in the patient group. RESULTS: Patients with CRPS showed reduced OR-BP in contralateral amygdala and parahippocampal gyri and increased OR-BP in contralateral prefrontal cortical areas. When OR-BP in the midcingulate cortex and the ipsilateral temporal cortex was low, the McGill pain rating index was high. In general, when anxiety and depression scales were high, contralateral temporal OR-BP was high as well. In addition, the anxiety scale decreased with increasing OR-BP in the contralateral parahippocampal cortex. CONCLUSIONS: These results demonstrate altered central opioidergic neurotransmission in CRPS. The correlation of regional opioid receptor availability to measures of pain, anxiety, and depression underlines the clinical importance of these findings.