Huygen, F.J.P.M.

A Multicenter, Prospective Trial to Assess the Safety and Performance of the Spinal Modulation Dorsal Root Ganglion Neurostimulator System in the Treatment of Chronic Pain (Article)

2013-05-16T00:00:00Z

Objectives: This multicenter prospective trial was conducted to evaluate the clinical performance of a new neurostimulation system designed to treat chronic pain through the electrical neuromodulation of the dorsal root ganglia (DRG) neurophysiologically associated with painful regions of the limbs and/or trunk. Materials and Methods: Thirty-two subjects were implanted with a novel neuromodulation device. Pain ratings during stimulation were followed up to six months and compared with baseline ratings. Subjects also completed two separate reversal periods in which stimulation was briefly stopped in order to establish the effects of the intervention. Results: At all assessments, more than half of subjects reported pain relief of 50% or better. At six months postimplant, average overall pain ratings were 58% lower than baseline (p<0.001), and the proportions of subjects experiencing 50% or more reduction in pain specific to back, leg, and foot regions were 57%, 70%, and 89%, respectively. When stimulation was discontinued for a short time, pain returned to baseline levels. Discrete coverage of hard-to-treat areas was obtained across a variety of anatomical pain distributions. Paresthesia intensity remained stable over time and there was no significant difference in the paresthesia intensity perceived during different body postures/positions (standing up vs. lying down). Conclusions: Results of this clinical trial demonstrate that neurostimulation of the DRG is a viable neuromodulatory technique for the treatment of chronic pain. Additionally, the capture of discrete painful areas such as the feet combined with stable paresthesia intensities across body positions suggest that this stimulation modality may allow more selective targeting of painful areas and reduce unwanted side-effects observed in traditional spinal cord stimulation (SCS).

Mast Cells: A New Target in the Treatment of Complex Regional Pain Syndrome? (Article)

2013-03-18T00:00:00Z

There is convincing evidence that inflammation plays a pivotal role in the pathophysiology of complex regional pain syndrome (CRPS). Besides inflammation, central sensitization is also an important phenomenon. Mast cells are known to be involved in the inflammatory process of CRPS and also play a role (at least partially) in the process of central sensitization. In the development of a more mechanism-based treatment, influencing the activity of mast cells might be important in the treatment of CRPS. We describe the rationale for using medication that counteracts the effects of mast cells in the treatment of CRPS.

The chronic pain conundrum: Should we CHANGE from relying on past history to assessing prognostic factors? (Article)

2012-02-01T00:00:00Z

Background: Despite limited empirical support, chronic pain has traditionally been defined mainly on the basis of its duration, which takes no account of the causative mechanisms or its clinical significance. Scope: For this commentary on current pain management practice, the CHANGE PAIN Advisory Board considered the evidence for adopting a prognostic definition of chronic pain. The rationale underlying this approach is to take psychological and behavioural factors into account, as well as the multidimensional nature of pain. Measures of pain intensity, interference with everyday activities, role disability, depression, duration and number of pain sites are used to calculate a risk score, which indicates the likelihood of a patient having pain in the future. The consistency of a prognostic definition with the concept of integrated patient care was also considered. Findings: When this method was compared with the number of pain days experienced over the previous 6 months in patients with back pain, headache or orofacial pain it was a better predictor of clinically significant pain 6 months later for all three pain conditions. Further evidence supporting this approach is that several factors other than the duration of pain have been shown to be important prognostic indicators, including unemployment, functional disability, anxiety and self-rated health. The use of a multifactorial risk score may also suggest specific measures to improve outcomes, such as addressing emotional distress. These measures should be undertaken as part of an integrated pain management strategy; chronic pain is a biopsychosocial phenomenon and all aspects of the patient's pain must be dealt with appropriately and simultaneously for treatment to be effective. Conclusion: The implementation of a prognostic definition and wider adoption of integrated care could bring significant advantages. However, these measures require improved training in pain management and structural revision of specialist facilities, for which political support is essential.

In Response: Intravenous Regional Guanethidine for Complex Regional Pain Syndrome (Article)

2011-09-01T00:00:00Z

24.Chronic Refractory Angina Pectoris (Article)

2011-09-01T00:00:00Z

Angina pectoris, cardiac pain associated with ischemia, is considered refractory when optimal anti-anginal therapy fails to resolve symptoms. It is associated with a decreased life expectancy and diminishes the quality of life. Spinal cord stimulation (SCS) may be considered for patients who have also undergone comprehensive interventions, such as coronary artery bypass graft (CABG) and percutaneous transluminal coronary angioplasty (PTCA) procedures. The mechanism of action of SCS is not entirely clear. Pain reduction is related to the increased release of inhibitory neuropeptides as well as normalization of the intrinsic nerve system of the heart muscle, and may have a protective myocardial effect. SCS in patients with refractory angina pectoris results in reduced anginal attacks as well as improved rate pressure product prior to the occurrence of ischemic events. This may be the result of reduced Myocardial Volume Oxygen (MVO2) and possibly the redistribution of the coronary blood flow to ischemic areas. There are a number of studies that demonstrate that SCS does not mask acute myocardial infarction. The efficacy of the treatment has been investigated in two prospective, randomized studies. The long-term results showed an improvement of the symptoms and of the quality of life. SCS can be an alternative to surgical intervention in a selected patient population. In addition, SCS is a viable option in patients in whom surgery is not possible. SCS is recommended in patients with chronic refractory angina pectoris that does not respond to conventional treatment and in whom revascularization procedures have been attempted or not possible, and who are optimized from a medical perspective. © 2011 The Authors. Pain Practice

23.Pain in Patients with Cancer (Article)

2011-09-01T00:00:00Z

Pain in patients with cancer can be refractory to pharmacological treatment or intolerable side effects of pharmacological treatment may seriously disturb patients' quality of life. Specific interventional pain management techniques can be an effective alternative for those patients. The appropriate application of these interventional techniques provides better pain control, allows the reduction of analgesics and hence improves quality of life. Until recently, the majority of these techniques are considered to be a fourth consecutive step following the World Health Organization's pain treatment ladder. However, in cancer patients, earlier application of interventional pain management techniques can be recommended even before considering the use of strong opioids. Epidural and intrathecal medication administration allow the reduction of the daily oral or transdermal opioid dose, while maintaining or even improving the pain relief and reducing the side effects. Cervical cordotomy may be considered for patients suffering with unilateral pain at the level below the dermatome C5. This technique should only be applied in patients with a life expectancy of less than 1year. Plexus coeliacus block or nervus splanchnicus block are recommended for the management of upper abdominal pain due to cancer. Pelvic pain due to cancer can be managed with plexus hypogastricus block and the saddle or lower end block may be a last resort for patients suffering with perineal pain. Back pain due to vertebral compression fractures with or without pathological tumor invasion may be managed with percutaneous vertebroplasty or kyphoplasty. All these interventional techniques should be a part of multidisciplinary patient program. © 2011 The Authors. Pain Practice

Evidence-Based Interventional Pain Medicine According to Clinical Diagnoses (Article)

2011-09-01T00:00:00Z

25.Ischemic Pain in the Extremities and Raynaud's Phenomenon (Article)

2011-09-01T00:00:00Z

Two important groups of disorders result from an insufficient blood supply to the extremities: critical vascular disease and the Raynaud's phenomenon. The latter can be subdivided into a primary and a secondary type. Critical ischemic disease is often caused by arteriosclerosis due to hypertension or diabetes. Primary Raynaud's is idiopathic and will be diagnosed as such if underlying systemic pathology has been excluded. Secondary Raynaud's is often a manifestation of a systemic disease. It is essential to try to establish a diagnosis as soon as possible in order to influence the evolution of the disease. A sympathetic nerve block can be considered in patients with critical ischemic vascular disease after extensive conservative treatment, preferably in the context of a study (2B±). If this has insufficient effect, spinal cord stimulation can be considered in a selected patient group (2B±). In view of the degree of invasiveness and the costs involved, this treatment should preferably be applied in the context of a study and with the use of transcutaneous pO2measurements. In case of primary Raynaud's, life style changes are the first step. Sympathectomy can be considered as a treatment of Raynaud's phenomenon (2C+), but only after multidisciplinary evaluation of the patient and in close consultation with the patient's rheumatologist, vascular surgeon or internist. © 2011 The Authors. Pain Practice

Anesthesiologists' views on using immune modulating drugs in pain medicine (Article)

2011-07-01T00:00:00Z

With few exceptions, anesthesiologists have not received training in the use of immune modulating drugs (IMDs); but recent evidence suggests that such drugs may be effective in reducing chronic pain. We therefore wished to learn how anesthesiologists working in pain medicine might envisage the treatment of their patients with IMDs in the future. We expected that anesthesiologists would want to refer patients for treatment with IMDs to medical colleagues, such as oncologists or rheumatologists, with prior experience in using these drugs, rather than treat these patients within their own practice. We conducted questionnaire surveys among anesthesiologists working in pain medicine in both the Netherlands and the U.K. to explore their views on using IMDs. Contrary to what we had expected, we found that a majority of the respondents would administer IMDs within their own practice, after appropriate training. The overall response rates were 30% and 23%, respectively; therefore, no firm conclusions can be drawn as to the views of the majority of practicing pain specialists. Our findings may have implications for the planning of both health service delivery and training in pain medicine. © 2010 The Authors. Pain Practice

21.Phantom pain (Article)

2011-07-01T00:00:00Z

Phantom pain is pain caused by elimination or interruption of sensory nerve impulses by destroying or injuring the sensory nerve fibers after amputation or deafferentation. The reported incidence of phantom limb pain after trauma, injury or peripheral vascular diseases is 60% to 80%. Over half the patients with phantom pain have stump pain as well. Phantom pain can also occur in other parts of the body; it has been described after mastectomies and enucleation of the eye. Most patients with phantom pain have intermittent pain, with intervals that range from 1day to several weeks. Even intervals of over a year have been reported. The pain often presents itself in the form of attacks that vary in duration from a few seconds to minutes or hours. In most cases, the pain is experienced distally in the missing limb, in places with the most extensive innervation density and cortical representation. Although there are still many questions as to the underlying mechanisms, peripheral as well as central neuronal mechanisms seem to be involved. Conservative therapy consists of drug treatment with amitriptyline, tramadol, carbamazepine, ketamine, or morphine. Based on the available evidence some effect may be expected from drug treatment. When conservative treatment fails, pulsed radiofrequency treatment of the stump neuroma or of the spinal ganglion (DRG) or spinal cord stimulation could be considered (evidence score 0). These treatments should only be applied in a study design. © 2011 The Authors. Pain Practice

22.Traumatic plexus lesion (Article)

2011-07-01T00:00:00Z

Pain, motor, and sensory deficits characterize patients with a traumatic lesion of the brachial plexus. Frequently, more severe injuries co-exist that require immediate surgical attention. Early rehabilitation and physical therapy are the cornerstones of treatment. Pharmacological management can be difficult. Surgical reconstruction is frequently advised when nerves are disrupted. The results, mostly from small historical reports, vary greatly. Neurostimulation may have an additional beneficial effect, especially if the pathophysiology of nociception and neuropathic pain becomes evident in these complex patients. © 2011 The Authors. Pain Practice

19. Carpal Tunnel Syndrome (Article)

2011-04-06T00:00:00Z

Carpal tunnel syndrome (CTS) is a common disorder. In the majority of cases, patients with CTS can be diagnosed by means of appropriate history taking. Nerve conduction examination of the nervus medianus is the most important additional diagnostic test and is the best predictor of symptom severity and functional status in idiopathic CTS. Treatment option depends on the severity of the symptoms and the degree of functional daily limitations. If few limitations are present, splinting or corticosteroid injections are preferred. Surgical interventions are reserved for the more severe conditions resulting in significant disability. Interventional pain treatment such as pulsed radiofrequency could be an addition to the future treatment options for CTS.Pain Practice

The association between psychological factors and the development of complex regional pain syndrome type 1 (CRPS1) - A prospective multicenter study (Article)

2011-04-04T00:00:00Z

The objective of this study was to investigate the association between psychological factors and complex regional pain syndrome type 1 (CRPS1). A prospective multicenter cohort study was performed involving the emergency room of three hospitals, and patients age 18 years or older, with a single fracture, were included in the study. At baseline (T0), participants completed a questionnaire covering demographic, psychological (Symptom Checklist-90), and medical variables. At plaster removal (T1) and at T2, the participants completed a questionnaire addressing symptoms of CRPS1. Psychological factors that were analysed were agoraphobia, depression, somatization, insufficiency, (interpersonal) sensitivity, insomnia, and life events. In total, 596 consecutive patients were included in the study, and 7.0% were diagnosed with CRPS1. None of the psychological factors predicted the development of CRPS1. The scores on the Symptom Checklist-90 subscales fell into the range of the general population and were, in most cases, average or below average when compared with those of pain patients or psychiatric patients. No empirical evidence supports a diagnosis of CRPS1 patients as psychologically different, and the current results indicate that there is no association between psychological factors and CRPS1.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-03-01T00:00:00Z

Invasive procedures for treatment of trigeminal neuralgia (TGN) include percutaneous radiofrequency thermocoagulation (PRT), partial sensory rhizotomy (PSR), and microvascular decompression (MVD). Using a nationwide discharge registry from The Netherlands, we assessed the frequency of use and patient characteristics, and evaluated treatment failure for each patient undergoing PRT, PSR, or MVD from January 2002 through December 2004. Only patients without a procedure in the year prior were included. Primary outcome was readmission for repeat procedures for TGN or known complications within 1 year. Comparability of patient populations was assessed through propensity scores based on hospital, age, sex, and comorbidity. Conditional logistic regression matched on propensity score was used to calculate relative risks (RR) with 95% confidence intervals (CIs) for repeat procedures or complications. During the study period, 672 patients with TGN underwent PRT, 39 underwent PSR, and 87 underwent MVD. Hospital type was the predominant determinant of procedure type; age, sex, and comorbidity were weak predictors. The RR for repeat procedures for PSR was 0.21 (95% CI: 0.07 to 0.65) and for MVD was 0.13 (95% CI: 0.05 to 0.35) compared with PRT (RR 1). For complications, the RR of PSR was 5.36 (95% CI: 1.46 to 19.64) and of MVD was 4.40 (95% CI: 1.44 to 13.42). Sex, urbanization, and comorbidity did not influence prognosis, but hospital and surgical volume did. In conclusion, although PSR and MVD are associated with a lower risk of repeat procedure than PRT, they seem to be more prone to complications requiring hospital readmission. Microvascular decompression and partial sensory rhizotomy are associated with a lower risk of undergoing a repeat procedure compared with percutaneous radiofrequency thermocoagulation but are more prone to complications requiring readmission to hospital.

18.Painful Diabetic Polyneuropathy (Article)

2011-03-01T00:00:00Z

In the industrialized world, polyneuropathy induced by diabetes mellitus (DM) is one of the most prevalent forms of neuropathy. Diabetic neuropathy can result from a direct toxic effect of glucose on nerve cells. Additionally, the damage of the nerve structures (central and peripheral) is accompanied by a microvascular dysfunction, which damages the vasa nervorum. More than 80% of the patients with DM-induced polyneuropathy have a distal and symmetric presentation. The initial symptoms are: signs of diminished sensation, burning feet, which may occur particularly during the night and worsen when touched, and tingling sensation in the feet. Attacks of shooting pain may also occur. Proper control of DM is mandatory. Based on the recently published National Institute for Health and Clinical Excellence guidelines, treatment of painful diabetic neuropathy should start with duloxetine or amitriptyline if duloxetine is contraindicated. If pain relief is inadequate, monotherapy with amitriptyline or pregabalin, or combination therapy with amitriptyline and pregabalin should be considered. If pain relief is still insufficient, tramadol instead of or in combination with a second-line agent should be considered. In patients who are unable to take oral medication, topical lidocaine can be considered for localized pain. There are currently four studies showing that spinal cord stimulation can potentially provide pain alleviation for the longer term in patients with painful diabetic polyneuropathy. Complications are mainly implant related, though infections also occur. The available evidence (2 C+) justifies spinal cord stimulation to be considered, preferably study related. © 2010 The Authors. Pain Practice

Distribution of signs and symptoms of Complex Regional Pain Syndrome type I in patients meeting the diagnostic criteria of the International Association for the Study of Pain (Article)

2011-02-21T00:00:00Z

The aim of the present study was to describe the occurrence of signs and symptoms in CRPS I patients meeting the IASP (Orlando) criteria, assess the occurrence of signs and symptoms in relation to disease duration and compare these to historical data based on a different diagnostic criteria set. Six hundred and ninety-two ambulatory patients meeting the IASP criteria for CRPS I referred to the outpatient clinics of five participating centers were included in this cross-sectional study. Characteristics were recorded in a standardized fashion and categorized according to the factor structure proposed by Bruehl/Harden. Subgroups were classified according to the duration of complaints and compared to historical data as described by Veldman et al. The Chi-square test corrected for multiple comparisons was used for statistical analysis. The prevalence of sensory signs was higher in patients with longer disease duration, especially for the allodynia's and hyperalgesia (all p < 0.001). Signs in vasomotor (color difference; p = 0.0007) and sudomotor (edema; p < 0.0001) subgroups were less frequently present in patients with longer disease duration (i.e. >6 months). Prevalences of signs in the motor subgroup were all higher (p < 0.0001) in patients with longer disease duration, except for limited range of motion. Occurrence of signs was significantly lower (<0.001) than those reported by Veldman et al., except for hyperesthesia and dystonia. Occurrence rates may vary at different time points after onset of CRPS, which may be of influence for diagnosing patients with novel derived diagnostic criteria. We argue for a mechanism based description of CRPS I based on one set of uniform generally accepted diagnostic criteria in future studies.

Pijn is van iedereen en van niemand (Inaugural Lecture)

2011-02-18T00:00:00Z

In deze rede zal ik laten zien waarom pijn van iedereen is: patiënten, artsen, zorgverzekeraars en beleidsmakers. Want ik constateer dat er nog steeds veel pijn wordt geleden en dat er te weinig wordt gedaan om dit op te lossen. Blijkbaar is pijn dus van niemand. Ik zal u uitleggen wat pijn is en wat we weten over het lijden van pijn. Ik bepleit dat pijn van iedereen moet worden en kom met voorstellen hoe dit te bereiken. Pijn is van iedereen en van niemand. Rede, uitgesproken ter gelegenheid van het aanvaarden van het ambt van bijzonder hoogleraar met als leeropdracht Anesthesiologie in het bijzonder pijngeneeskunde, aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam op 18 februari 2011

Make a CHANGE: Optimising communication and pain management decisions (Article)

2011-02-01T00:00:00Z

The major objectives of the CHANGE PAIN International Advisory Board are to enhance understanding of chronic pain and to develop strategies for improving pain management. At its second meeting, in November 2009, evidence was presented that around one person in five in Europe and the USA experiences chronic pain, and the delay before referral to a pain specialist is often several years. Moreover, physicians' pharmacological approach to chronic pain is inconsistent, as evidenced by the huge variation in treatment between different European countries. It was agreed that efficient communication between physician and patient is essential for effective pain management, and that efficacy/side-effect balance is a key factor in choosing an analgesic agent. The multifactorial nature of chronic pain produces various physical and psychological symptoms, so the management of chronic pain should be tailored to the individual. Pharmacological therapy must be matched to the causative mechanisms responsible, or it is likely to prove ineffective and risk the development of a 'vicious circle'; doses are increased because of inadequate pain relief, but this increases side-effects so doses are reduced, pain relief is then inadequate, so doses are increased, and so on. Pain management decisions should not therefore be based solely on the severity of pain. Based on the concept of individual treatment targets (ITT), the CHANGE PAIN Scale was adopted a simple, user-friendly assessment tool to improve communication between physician and patient. The 11-point NRS enables the patient to rate the current pain intensity and to set a realistic individual target level. On the reverse are six key parameters affecting the patient's quality of life; clinicians simply need to agree with patients whether improvement is needed in each one. Regular use can establish the efficacy and tolerability of pain management, and the rate of progress towards individual treatment targets.

A nationwide study of three invasive treatments for trigeminal neuralgia (Article)

2011-01-01T00:00:00Z

16. Complex Regional Pain Syndrome (Article)

2011-01-01T00:00:00Z

Complex regional pain syndrome (CRPS), formerly known as reflex sympathetic dystrophy is a pain syndrome with an unclear pathophysiology and unpredictable clinical course. The disease is often therapy resistant, the natural course not always favorable. The diagnosis of CRPS is based on signs and symptoms derived from medical history and physical examination. Pharmacological pain management and physical rehabilitation of limb function are the main pillars of therapy and should be started as early as possible. If, however, there is no improvement of limb function and persistent severe pain, interventional pain management techniques may be considered.Intravenous regional blocks with guanethidine did not prove superior to placebo but frequent side effects occurred.Therefore this technique receives a negative recommendation (2 A-). Sympathetic block is the interventional treatment of first choice and has a 2 B+ rating. Ganglion stellatum (stellate ganglion) block with repeated local anesthetic injections or by radiofrequency denervation after positive diagnostic block is documented in prospective and retrospective trials in patients suffering from upper limb CRPS. Lumbar sympathetic blocks can be performed with repeated local anesthetic injections. For a more prolonged lumbar sympathetic block radiofrequency treatment is preferred over phenol neurolysis because effects are comparable whereas the risk for side effects is lower (2 B+). For patients suffering from CRPS refractory to conventional treatment and sympathetic blocks, plexus brachialis block or continuous epidural infusion analgesia coupled with exercise therapy may be tried (2 C+). Spinal cord stimulation is recommended if other treatments fail to improve pain and dysfunction (2 B+). Alternatively peripheral nerve stimulation can be considered, preferentially in study conditions (2 C+). © 2010 The Authors. Pain Practice

Diagnostic criteria in patients with complex regional pain syndrome assessed in an out-patient clinic (Article)

2010-08-01T00:00:00Z

Background: Specific criteria have been described and accepted worldwide for diagnosing patients with complex regional pain syndrome (CRPS). Nevertheless, a clear-cut diagnosis cannot be confirmed in a number of cases. Aim: The objective of this study was to investigate the effectiveness of the described diagnostic criteria used by several clinical disciplines. Methods: We included 195 patients who were referred to our pain clinic within a period of 1 year. Data were collected on patient characteristics, signs, symptoms, disease-related medication, and the background of the referring clinicians. Results: The Harden and Bruehl criteria were confirmed in 95 patients (49%). These patients used a higher than average number of analgesics, opiates, and anti-oxidants, and frequently received prescriptions for benzodiazepines instead of anti-depressants. The mean disease duration was 29 ± 4.6 months and the mean visual analogue score for pain was 8.1 ± 0.19. A subgroup of patients had a colder temperature in the affected extremity compared with the unaffected extremity. This subgroup showed a longer disease duration and higher visual analogue scale pain. Conclusion: The diagnostic criteria used to determine CRPS should be further improved. A large number of referred patients experienced substantial pain, without receiving adequate medication. Disease-related medication is unrelated to CRPS-specific disease activity. Knowledge of underlying mechanisms is warranted before an adequate pharmaceutical intervention can be considered.

9. Painful shoulder complaints. (Article)

2010-07-01T00:00:00Z

Painful shoulder complaints have a high incidence and prevalence. The etiology is not always clear. Clinical history and the active and passive motion examination of the shoulder are the cornerstones of the diagnostic process. Three shoulder tests are important for the examination of shoulder complaints: shoulder abduction, shoulder external rotation, and horizontal shoulder adduction. These tests can guide the examiner to the correct diagnosis. Based on this diagnosis, in most cases, primarily a conservative treatment with nonsteroidal anti-inflammatory drugs possibly in combination with manual and/or exercise therapy can be started. When conservative treatment fails, injection with local anesthetics and corticosteroids can be considered. In the case of frozen shoulder, a continuous cervical epidural infusion of local anesthetic and small doses of opioids or a pulsed radiofrequency treatment of the nervus suprascapularis can be considered.

Pharmacological treatment of chronic pain the need for CHANGE (Article)

2010-05-01T00:00:00Z

Background: Although chronic pain affects around 20 of adults in Europe and the USA, there is substantial evidence that it is inadequately treated. In June 2009, an international group of pain specialists met in Brussels to identify the reasons for this and to achieve consensus on strategies for improving pain management. Scope: Literature on chronic pain management was reviewed, and information presented to and discussed by a panel of experts. Findings: It was agreed that guidelines are not universally accepted by those involved in pain management, and pain treatment seems to be driven mainly by tradition and personal experience. Other factors include poor communication between patients and physicians, the side effects of analgesic drugs, and limited individualisation of therapy. Difficulty in maintaining the balance between adequate pain relief and acceptable tolerability, particularly with strong opioids, can lead to the establishment of a vicious circle that alternates between lack of efficacy and unpleasant side effects, prompting discontinuation of treatment. The medical communitys understanding of the physiological differences between nociceptive pain and neuropathic pain, which is often more severe and difficult to treat, could be improved. Increasing physicians knowledge of the pharmacological options available to manage these different pain mechanisms offers the promise of better treatment decisions and more widespread adoption of a multi-mechanistic approach; this could involve loosely combining two substances from different drug classes, or administering an analgesic with two different mechanisms of action. In some circumstances, a single compound capable of addressing both nociceptive and neuropathic pain is desirable. Conclusions: To improve patient outcomes, a thorough understanding of pain mechanisms, sensitisation and multi-mechanistic management is required. Universal, user-friendly educational tools are therefore required to familiarise physicians with these topics, and also to improve communication between physicians and their pain patients, so that realistic expectations of treatment can be established.

Spontaneous onset of Complex Regional Pain Syndrome (Article)

2010-05-01T00:00:00Z

Complex Regional Pain Syndrome (CRPS) usually develops after a noxious event, but spontaneous onsets have been described in 3-11% of the cases. The existence of spontaneous-onset CRPS is highly debated and the aim of the present study was therefore to compare the phenotypic characteristics of CRPS patients with a spontaneous onset, with those of patients with a trauma-induced onset. Data of 537 CRPS patients followed up at four departments of anesthesiology were analyzed and comprised 498 (93%) patients with and 39 (7%) patients without a known eliciting event. There where no significant differences between the two groups in gender, or in onset in upper or lower limb or left or right side of the body. Compared to CRPS patients with a trauma-induced onset, spontaneous-onset cases were on average 9 years younger at disease onset and had a 1.4 years longer median disease duration. No significant differences in frequency were found for any of the 34 compared signs and symptoms when the effect of multiple testing was controlled. In conclusion, CRPS may develop both with and without a precipitating noxious event, with both groups exhibiting a largely similar clinical presentation. Spontaneous-onset CRPS patients generally develop the syndrome at a younger age, possibly indicating a susceptibility to develop the condition. The longer disease duration in spontaneous-onset cases may reflect a more gradual disease onset, poorer prognosis, or a delay in diagnosis, possibly as a result of reluctance to make this diagnosis in the absence of a clear initiating event.

Use of oral ketamine in chronic pain management: A review (Article)

2010-05-01T00:00:00Z

The analgesic effect of ketamine is primarily based on the antagonism of the N-methyl-d-aspartate (NMDA) receptor. Activation of NMDA receptors may play a crucial role in the pathogenesis of chronic pain. Little formal research has been performed on the efficacy and safety of ketamine in chronic pain, especially concerning long-term oral administration. This review provides an overview of the available clinical data on the use of oral ketamine in chronic pain management. A literature search was performed in MEDLINE, EMBASE and the Cochrane Library, resulting in 22 relevant articles. Because most retrieved articles were of a descriptive nature (e.g. case reports and case series) a quantitative analysis was not possible. There was no consistent dose-response relation. A recommended starting dosage in ketamine-naive patients is 0.5 mg/kg racemic ketamine or 0.25 mg/kg S-ketamine as a single oral dose. The dosage is increased by the same amount if required. For a continuous analgesic effect it is usually given 3-4 times daily. The injection fluid can be taken orally. When parenteral ketamine is switched to oral administration the daily dosage can be kept equal and, depending on clinical effect and/or adverse effects, is slowly increased. The pharmacologically active metabolite norketamine is believed to contribute to the analgesic effect of oral ketamine. Lack of evidence regarding efficacy, and the poor safety profile, do not support routine use of oral ketamine in chronic pain management. Oral ketamine may have a limited place as add-on therapy in complex chronic pain patients if other therapeutic options have failed.

Autofluorescent flavoprotein imaging of spinal nociceptive activity (Article)

2010-03-17T00:00:00Z

Pain arises from activation of peripheral nociceptors, and strong noxious stimuli may cause an increase in spinal excitability called central sensitization, which is likely involved in many pathological pain states. So far, it has not been achieved to simultaneously visualize in vivo both the temporal and spatial aspects of spinal activity, including central sensitization. Using autofluorescent flavoprotein imaging (AFI), an optical technique suitable for mapping activity in nervous tissue, we demonstrate a close temporal and spatial correlation of electrically evoked nociceptive input with the spinal AFI signal, representing spinal neuronal activity. The AFI signal increases linearly with stimulation intensity. Furthermore, we found that the AFI signal was much larger in intensity and size when the same electrical stimulation was applied after the induction of central sensitization by a subcutaneous capsaicin injection. Finally, innocuous palpation of the hindpaw did not evoke an AFI response in naive animals, but after capsaicin injection a strong response was obtained. This is the first report demonstrating simultaneously the temporal and spatial propagation of spinal nociceptive activity in vivo. Copyright

Pharmacological Treatment of Neuropathic Facial Pain in the Dutch General Population (Article)

2010-03-01T00:00:00Z

Few drugs are registered for treatment of neuropathic facial pain (NFP), and not much is known about treatment choices for NFP in daily practice. Patients with NFP were identified in the IPCI-database with longitudinal electronic general practitioner (GP) records. We described prescription patterns of pain medication following first symptoms. Off-label, off-guideline use, failure and reasons for failure were assessed. Failure was defined as treatment switch, exacerbation, adverse event, or invasive treatment for NFP. Of 203 NFP cases, 160 (79%) received pharmacological pain treatment. Most patients (90%) were initially treated by a GP with anti-epileptic drugs (55%) or NSAIDs (16%) as monotherapy. The median treatment delay was 0 days (range 0 to 2,478 days). Adverse events were experienced by 16 (10%) of patients. Sixty-two percent of first prescriptions were in adherence to guidelines and 59% were considered on-label while 34% of prescriptions were both off-label and off-guideline. Of the first therapy, 38% failed within 3 months. The median duration until failure was 251 days. General practitioners usually are the first to treat NFP. They usually prescribe drugs licensed for NFP and according to guidelines, but the extent of off-label use is substantial. Initial treatment often failed within a short period after starting therapy. Perspective: This drug-utilization study describes the pharmacological treatment of different forms of neuropathic facial pain in daily practice. Although treatment is mostly initiated rapidly by general practitioners in a correct way, it often contains off-label or off-guideline medication. Failure of the initial treatment is common and occurs rapidly as well.

Linguistic validation of the DN4 for use in international studies (Article)

2010-01-01T00:00:00Z

Objectives: Traditionally, pain is divided into two main groups: nociceptive pain due to an excess of nociception and neuropathic pain associated with an injury or dysfunction of the central or peripheral nervous system. The French neuropathic pain group has developed a specific questionnaire, the DN4, to help clinicians in the differential diagnosis of neuropathic and non-neuropathic pain. In order to allow this questionnaire to be used in international studies, it has been translated and linguistically validated into Dutch, German, Greek and Hungarian, using a well-established procedure. Methods: The same method was used for each country and involved four stages: (1) two forward translations followed by comparison and reconciliation of the translations, (2) one backward translation, (3) review by an expert clinician, and (4) cognitive testing of the first seven items on patients. Results: The translation work produced three types of situations. Either the original wording could be translated literally or semantic issues were discussed as the original wording was not always sufficiently clear and had to be clarified by adding an explanation, or, in the case of idiomatic phrases such as "pins and needles", it was necessary to use different expressions, the challenge being to retain the original concept while doing so. The versions proposed to patients and experts were well understood. Conclusion: The DN4 items were linguistically validated in each of the target languages, thus providing the means for standardising the diagnosis of neuropathic pain and pooling the data collected during clinical research in the different countries involved.

Incidence of facial pain in the general population (Article)

2009-12-15T00:00:00Z

Facial pain has a considerable impact on quality of life. Accurate incidence estimates in the general population are scant. The aim was therefore to estimate the incidence rate (IR) of trigeminal neuralgia (TGN), postherpetic neuralgia (PHN), cluster headache (CH), occipital neuralgia (ON), local neuralgia (LoN), atypical facial pain (AFP), glossopharyngeal neuralgia (GPN) and paroxysmal hemicrania (PH) in the Netherlands. In the population-based Integrated Primary Care Information (IPCI) medical record database potential facial pain cases were identified from codes and narratives. Two medical doctors reviewed medical records, questionnaires from general practitioners and specialist letters using criteria of the International Association for the Study of Pain. A pain specialist arbitrated if necessary and a random sample of all cases was evaluated by a neurologist. The date of onset was defined as date of first specific symptoms. The IR was calculated per 100,000 PY. Three hundred and sixty-two incident cases were ascertained. The overall IR [95% confidence interval] was 38.7 [34.9-42.9]. It was more common among women compared to men. Trigeminal neuralgia and cluster headache were the most common forms among the studied diseases. Paroxysmal hemicrania and glossopharyngeal neuralgia were among the rarer syndromes. The IR increased with age for all diseases except CH and ON, peaking in the 4th and 7th decade, respectively. Postherpetic neuralgia, CH and LoN were more common in men than women. From this we can conclude that facial pain is relatively rare, although more common than estimated previously based on hospital data.

Regulation of peripheral blood flow in complex regional pain syndrome: Clinical implication for symptomatic relief and pain management (Article)

2009-11-04T00:00:00Z

Background. During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. Discussion. The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. Summary. The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients.

Role of NFκB in an Animal Model of Complex Regional Pain Syndrome-type I (CRPS-I) (Article)

2009-11-01T00:00:00Z

NFκB is involved in several pathogenic mechanisms that are believed to underlie the complex regional pain syndrome (CRPS), including ischemia, inflammation and sensitization. Chronic postischemia pain (CPIP) has been developed as an animal model that mimics the symptoms of CRPS-I. The possible involvement of NFκB in CRPS-I was studied using CPIP rats. Under sodium pentobarbital anesthesia, a tourniquet was placed around the rat left ankle joint, producing 3 hours of ischemia, followed by rapid reperfusion (IR injury). NFκB was measured in nuclear extracts of muscle and spinal cord tissue using ELISA. Moreover, the anti-allodynic (mechanical and cold) effect was tested for systemic, intrathecal, or intraplantar treatment with the NFκB inhibitor pyrrolidine dithiocarbamate (PDTC). At 2 and 48 hours after IR injury, NFκB was elevated in muscle and spinal cord of CPIP rats compared to shams. At 7 days, NFκB levels were normalized in muscle, but still elevated in spinal cord tissue. Systemic PDTC treatment relieved mechanical and cold allodynia in a dose-dependent manner, lasting for at least 3 hours. Intrathecal-but not intraplantar-administration also relieved mechanical allodynia. The results suggest that muscle and spinal NFκB plays a role in the pathogenesis of CPIP and potentially of human CRPS. Perspective: Using the CPIP model, we demonstrate that NFκB is involved in the development of allodynia after a physical injury (ischemia and reperfusion) without direct nerve trauma. Since CPIP animals exhibit many features of human CRPS-I, this observation indicates a potential role for NFκB in human CRPS.

No Recovery of Cold Complex Regional Pain Syndrome After Transdermal Isosorbide Dinitrate: A Small Controlled Trial (Article)

2009-09-01T00:00:00Z

The microcirculation appears to be impaired in cold chronic complex regional pain syndrome (CRPS). This double-blind, placebo-controlled, randomized trial investigated the effect of the nitric oxide (NO) donor isosorbide dinitrate (ISDN) on the peripheral blood flow in patients with chronic CRPS. Twenty-four patients received 1% ISDN in Vaseline®or a placebo ointment applied to the dorsum of the affected hand four times daily for 10 weeks. The patients participated in a physical therapy program to improve activity. The primary outcome measure was blood distribution in the affected extremity, which was determined by measuring the skin temperature using videothermography. We also measured NO and endothelin-1 concentrations in blister fluid, pain using the visual analog scale, and activity limitations using an upper limb activity monitor and the Disabilities of Arm Shoulder and Hand Questionnaire. ISDN failed to produce a significant improvement in temperature asymmetry in chronic cold CRPS patients, and it did not result in the expected reduction in pain and increase in activity compared with placebo either. There may be other central or peripheral factors contributing to the disturbed vasodynamics in cold chronic CRPS that are not influenced by NO substitution. This study does not show an improvement of the regional blood distribution by ISDN in the involved extremity of patients with cold-type CRPS.

Is there an association between psychological factors and the Complex Regional Pain Syndrome type 1 (CRPS1) in adults? A systematic review (Article)

2009-09-01T00:00:00Z

Complex Regional Pain Syndrome type 1 (CRPS1) is a complication after trauma or surgery. Its pathophysiology is still a matter of debate, and psychological factors have been suggested to play a role, although their influence is unclear. The aim of this study was to investigate the evidence for the influence of psychological factors on the onset and maintenance of CRPS1 in adults. In a systematic review, articles were selected using Cochrane, Pubmed/Medline, Psychinfo, and Cinahl since 1980. Only original articles and empirical studies were included. Based on these selection criteria, 31 articles were identified. Studies were evaluated and weighted using a quality assessment instrument. The few prospective studies do not report a relationship between CRPS1 and depression, anxiety, neuroticism, or anger. The results of the retrospective/cross-sectional studies yield contradictory results regarding psychological problems in patients with CRPS1. A majority show no association, and studies with a higher methodological quality lean to a conclusion of no relationship between psychological factors and CRPS1. The majority of included studies (N = 24; 77%) had only a poor to moderate methodological quality. Although many patients with CRPS1 are stigmatized as being psychologically different, this literature review identified no relationship between CRPS1 and several psychological factors. Only life events seemed to be associated with CRPS1: patients who experienced more life events appeared to have a greater chance of developing CRPS1. More studies with greater methodological quality and more participants should be performed on the association between psychological factors and the development and course of CRPS1.

Outcome of the complex regional pain syndrome (Article)

2009-09-01T00:00:00Z

Objectives: The outcome of complex regional pain syndrome (CRPS) is relatively unknown. High disease resolution rates have been reported, but also long-lasting impairments in many patients. This study aims to assess CRPS outcome in a population-based cohort of CRPS patients. Methods: CRPS patients were retrospectively identified (1996 to 2005) in a Dutch general practitioners database, the integrated primary care information project, and included if at onset (ie, in the past) they had complied with the International Association for the Study of Pain (IASP) diagnostic criteria. The disease status at minimum of 2 years since onset was assessed during visits using questionnaires, interviews, and physical examination. Symptoms and signs were compared with reference patients with an identical past injury but without CRPS. Actual fulfillment of the IASP criteria, treatment status, self-reported recovery, and working status were recorded. Moreover, to identify the potential prognostic factors, baseline patient characteristics were compared across subgroups according to the CRPS outcome. These subgroups were derived by cluster analysis on actual symptoms and signs. Results: One hundred and two CRPS patients were assessed at on average 5.8 years (range: 2.1 to 10.8) since onset. CRPS patients displayed higher symptom and sign prevalences in all categories (sensory, vasomotor, sudomotor, and motor/trophic) than controls. Sixteen percent (95% CI: 9-22) reported the CRPS as still progressive, whereas 31% (95% CI: 19-43) were incapable of working. Patients in the poorest outcome cluster more often had their upper extremity affected, event other than a fracture, and cold CRPS. Discussion: Severe CRPS outcome is rare, but a majority of patients has persistent impairments at 2 or more years since onset.

Referral and treatment patterns for complex regional pain syndrome in the Netherlands (Article)

2009-07-01T00:00:00Z

Background: Patients with complex regional pain syndrome (CRPS) are seen and treated by a variety of physicians. The present study aims to describe referral and treatment patterns for CRPS patients in the Netherlands. Methods: Patients, who were selected (1996-2005) from an electronic general practice (GP) database (Integrated Primary Care Information Project), were invited for study participation, involving diagnosis verification (International Association for the Study of Pain criteria) and assessment of referrals and treatment through information retrieved from GP journals, patients' questionnaires, pharmacy dispensing lists and specialist letters if available. Results: One hundred and two patients were included. Sixty-one percent had presented first at the GP, while 80% subsequently consulted one or more medical specialists, most frequently an anesthetist (55% of the cases) or a specialist in rehabilitation medicine (41%). Over 90% of the patients received oral or topical pharmacotherapy, 45% received intravenous therapy, 89% received non-invasive therapy (i.e. physiotherapy) and 18% received nerve blocks. Analgesics and free radical scavengers were administered early during CRPS, while vasodilating drugs and drugs against neuropathic pain (antidepressants and anti-epileptics) were administered later on. Pharmacotherapy was usually initiated by a medical specialist. Conclusion: The Dutch treatment guidelines, issued in 2006, recommend free radical scavenger prescription (plus physiotherapy) as the initial treatment step for CRPS. Until 2005 only half of the patients received a scavenger within 3 months after disease onset, and the majority presents first at the GP, in particular GPs may be encouraged to initiate treatment with scavengers, while waiting for the results of further specialist consultation.

The association between ACE inhibitors and the complex regional pain syndrome: Suggestions for a neuro-inflammatory pathogenesis of CRPS (Article)

2009-04-01T00:00:00Z

Antihypertensive drugs interact with mediators that are also involved in complex regional pain syndrome (CRPS), such a neuropeptides, adrenergic receptors, and vascular tone modulators. Therefore, we aimed to study the association between the use of antihypertensive drugs and CRPS onset. We conducted a population-based case-control study in the Integrated Primary Care Information (IPCI) database in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during an expert visit (using IASP criteria), or if they had been diagnosed by a medical specialist. Up to four controls per cases were selected, matched on gender, age, calendar time, and injury. Exposure to angiotensin converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, β-blockers, calcium channel blockers, and diuretics was assessed from the automated prescription records. Data were analyzed using multivariate conditional logistic regression. A total of 186 cases were matched to 697 controls (102 confirmed during an expert visit plus 84 with a specialist diagnosis). Current use of ACE inhibitors was associated with an increased risk of CRPS (ORadjusted: 2.7, 95% CI: 1.1-6.8). The association was stronger if ACE inhibitors were used for a longer time period (ORadjusted: 3.0, 95% CI: 1.1-8.1) and in higher dosages (ORadjusted: 4.3, 95% CI: 1.4-13.7). None of the other antihypertensive drug classes was significantly associated with CRPS. We conclude that ACE inhibitor use is associated with CRPS onset and hypothesize that ACE inhibitors influence the neuro-inflammatory mechanisms that underlie CRPS by their interaction with the catabolism of substance P and bradykinin.

Current understandings on complex regional pain syndrome (Article)

2009-03-10T00:00:00Z

The mechanisms underlying complex regional pain syndrome (CRPS) have been increasingly studied over the past decade. Classically, this painful and disabling disorder was considered to emerge from pathology of the central nervous system. However, the involvement of additional peripheral disease mechanisms is likely, and recently these mechanisms have also attracted scientific attention. The present article provides an overview of the current understandings regarding pathology of the autonomic and somatic nervous system in CRPS, as well as the roles of neurogenic inflammation, hypoxia, and the contribution of psychological factors. Potential connections between the separate disease mechanisms will be discussed. Additionally, currently known risk factors for CRPS will be addressed. Insight into risk factors is of relevance as it facilitates early diagnosis and tailored treatment. Moreover, it may provide clues for further unraveling of the pathogenesis and etiology of CRPS.

Estrogens and the risk of complex regional pain syndrome (CRPS) (Article)

2009-03-09T00:00:00Z

Objective: Since complex regional pain syndrome (CRPS) shows a clear female predominance, we investigated the association between the cumulative as well as current exposure to estrogens, and CRPS. Methods: A population-based case-control study was conducted in the Integrated Primary Care Information (IPCI) project in the Netherlands. Cases were identified from electronic records (1996-2005) and included if they were confirmed during a visit (using International Association for the Study of Pain Criteria), or had been diagnosed by a specialist. Controls were matched to cases on gender, age, calendar time, and injury. Measures of cumulative endogenous estrogen exposure were obtained by questionnaire and included age of menarche and menopause, menstrual life, and cumulative months of pregnancy and breast-feeding. Current estrogen exposure at CRPS onset was retrieved from the electronic medical records and determined by current pregnancy or by the use of oral contraceptive (OC) drugs or hormonal replacement therapy (HRT). Results: Hundred and forty-three female cases (1493 controls) were included in analyses on drug use and pregnancies, while cumulative endogenous estrogen exposure was studied in 53 cases (58 controls) for whom questionnaire data were available. There was no association between CRPS and either cumulative endogenous estrogen exposure, OC, or HRT use. CRPS onset was increased during the first 6 months after pregnancy (OR: 5.6, 95%CI: 1.0-32.4), although based on small numbers. Discussion: We did not find an association between CRPS onset and cumulative endogenous estrogen exposure or current OC or HRT use, but more powered studies are needed to exclude potential minor associations. Copyright

IgE-mediated hypersensitivity: Patients with complex regional pain syndrome type 1 (CRPS1) vs the Dutch population. A retrospective study (Article)

2009-02-12T00:00:00Z

Objective. To investigate whether hypersensitivity is more common in Complex Regional Pain Syndrome type 1 (CRPS1) patients than in the general population. In a recent study, the level of tryptase, a specific marker for mast cells, was significantly higher in blister fluid from the involved extremity of CRPS1 patients. This suggested that mast cells may play a role in the pathophysiology of CRPS1. Mast cells are major effectors in allergic reactions, and are also involved in a variety of noninfectious inflammatory diseases. Patients. Sixty-six Dutch patients with CRPS1 in one extremity were included. Outcome Measures. Allergy information was obtained from the medical history and a modified questionnaire based on the Europees Luchtweg Onderzoek Nederland 1 study. Total IgE and allergen-specific IgE were measured from blood samples. Also tryptase, as a marker for mast cells, was measured. The data from the questionnaire were compared with that of the general Dutch population, and the plasma levels were compared with reference values and data in the literature. Results. The medical history did not differ from information provided in the questionnaire by the CRPS1 group. There was no significant difference between the answers to the questionnaire between the CRPS1 patients and the general population. The total IgE levels were elevated in 30% of the CRPS1 patients compared with 15 - 24% of the general population, and allergen-specific IgE and tryptase levels were comparable with the reference values. Conclusions. Based on the medical history, an allergy questionnaire, and objective laboratory findings we conclude that IgE-mediated hypersensitivity is not more common in CRPS1 patients than in the general population.

Effect of tadalafil on blood flow, pain, and function in chronic cold Complex Regional Pain Syndrome: A randomized controlled trial (Article)

2008-11-06T00:00:00Z

Background. This double-blind, randomized, controlled trial investigated the effect of the phosphodiesterase-5 inhibitor tadalafil on the microcirculation in patients with cold Complex Regional Pain Syndrome (CRPS) in one lower extremity. Methods. Twenty-four patients received 20 mg tadalafil or placebo daily for 12 weeks. The patients also participated in a physical therapy program. The primary outcome measure was temperature difference between the CRPS side and the contralateral side, determined by measuring the skin temperature with videothermography. Secondary outcomes were: pain measured on a Visual Analogue Scale, muscle force measured with a MicroFet 2 dynamometer, and level of activity measured with an Activity Monitor (AM) and walking tests. Results. At the end of the study period, the temperature asymmetry was not significantly reduced in the tadalafil group compared with the placebo group, but there was a significant and clinically relevant reduction of pain in the tadalafil group. Muscle force improved in both treatment groups and the AM revealed small, non-significant improvements in time spent standing, walking, and the number of short walking periods. Conclusion. Tadalafil may be a promising new treatment for patients that have chronic cold CRPS due to endothelial dysfunction, and deserves further investigation. Trial Registration. The registration number in the Dutch Trial Register is ISRCTN60226869.

Cutaneous tactile allodynia associated with microvascular dysfunction in muscle (Article)

2008-10-28T00:00:00Z

Background: Cutaneous tactile allodynia, or painful hypersensitivity to mechanical stimulation of the skin, is typically associated with neuropathic pain, although also present in chronic pain patients who do not have evidence of nerve injury. We examine whether deep tissue microvascular dysfunction, a feature common in chronic non-neuropathic pain, contributes to allodynia. Results: Persistent cutaneous allodynia is produced in rats following a hind paw ischemia-reperfusion injury that induces microvascular dysfunction, including arterial vasospasms and capillary slow flow/ no-reflow, in muscle. Microvascular dysfunction leads to persistent muscle ischemia, a reduction of intraepidermal nerve fibers, and allodynia correlated with muscle ischemia, but not with skin nerve loss. The affected hind paw muscle shows lipid peroxidation, an upregulation of nuclear factor kappa B, and enhanced pro-inflammatory cytokines, while allodynia is relieved by agents that inhibit these alterations. Allodynia is increased, along with hind paw muscle lactate, when these rats exercise, and is reduced by an acid sensing ion channel antagonist. Conclusion: Our results demonstrate how microvascular dysfunction and ischemia in muscle can play a critical role in the development of cutaneous allodynia, and encourage the study of how these mechanisms contribute to chronic pain. We anticipate that focus on the pain mechanisms associated with microvascular dysfunction in muscle will provide new effective treatments for chronic pain patients with cutaneous tactile allodynia.

Medical history and the onset of complex regional pain syndrome (CRPS) (Article)

2008-10-15T00:00:00Z

Knowledge concerning the medical history prior to the onset of complex regional pain syndrome (CRPS) might provide insight into its risk factors and potential underlying disease mechanisms. To evaluate prior to CRPS medical conditions, a case-control study was conducted in the Integrated Primary Care Information (IPCI) project, a general practice (GP) database in the Netherlands. CRPS patients were identified from the records and validated through examination by the investigator (IASP criteria) or through specialist confirmation. Cases were matched to controls on age, gender and injury type. All diagnoses prior to the index date were assessed by manual review of the medical records. Some pre-specified medical conditions were studied for their association with CRPS, whereas all other diagnoses, grouped by pathogenesis, were tested in a hypothesis-generating approach. Of the identified 259 CRPS patients, 186 cases (697 controls) were included, based on validation by the investigator during a visit (102 of 134 visited patients) or on specialist confirmation (84 of 125 unvisited patients). A medical history of migraine (OR: 2.43, 95% CI: 1.18-5.02) and osteoporosis (OR: 2.44, 95% CI: 1.17-5.14) was associated with CRPS. In a recent history (1-year before CRPS), cases had more menstrual cycle-related problems (OR: 2.60, 95% CI: 1.16-5.83) and neuropathies (OR: 5.7; 95% CI: 1.8-18.7). In a sensitivity analysis, including only visited cases, asthma (OR: 3.0; 95% CI: 1.3-6.9) and CRPS were related. Psychological factors were not associated with CRPS onset. Because of the hypothesis-generating character of this study, the findings should be confirmed by other studies.

Expression of endothelial nitric oxide synthase and endothelin-1 in skin tissue from amputated limbs of patients with complex regional pain syndrome (Article)

2008-08-11T00:00:00Z

Background and Objectives. Impaired microcirculation during the chronic stage of complex regional pain syndrome (CRPS) is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Endothelial dysfunction is suggested to be the main cause of diminished blood flow. The aim of this study was to examine the distribution of endothelial nitric oxide synthase (eNOS) and endothelin-1(ET-1) relative to vascular density represented by the endothelial marker CD31-immunoreactivity in the skin tissue of patients with chronic CRPS. Methods. We performed immunohistochemical staining on sections of skin specimens obtained from the amputated limbs (one arm and one leg) of two patients with CRPS. Results. In comparison to proximal specimens we found an increased number of migrated endothelial cells as well as an increase of eNOS activity in distal dermis specimens. Conclusions. We found indications that endothelial dysfunction plays a role in chronic CRPS. Copyright

Tumor necrosis factor-α and interleukin-6 are not correlated with the characteristics of Complex Regional Pain Syndrome type 1 in 66 patients (Article)

2008-08-01T00:00:00Z

It was previously shown in a group of 9 patients with complex regional pain syndrome type 1 (CRPS1) that levels of the proinflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) are higher in blister fluid from the involved side. We hypothesize that local inflammation is responsible for the characteristics of CRPS1. The aim of this study was to confirm the previous observation in a large group of CRPS1 patients, repeating the measurement of TNF-α and IL-6 in blister fluid. Furthermore, we sought to determine whether these cytokines are responsible for the characteristics of CRPS1 and characterize the relationship between cytokine levels and duration of the disease. Sixty-six patients with CRPS1 participated. Skin blisters were artificially induced for measurement of cytokines in both extremities. The following disease characteristics were assessed: pain and differences in temperature, volume, and mobility between the extremities. TNF-α and IL-6 levels were significantly higher in blister fluid from the involved side. However, cytokine levels did not correlate with the characteristics or duration of the disease. Our findings confirm the presence of local inflammation in a population of 66 patients in the first 2 years of CRPS1. Proinflammatory cytokines seem to be only partly involved in the pathophysiology of CRPS1, as indicated by the lack of coherence between TNF-α and IL-6 levels and the signs and symptoms of inflammation and disease duration. Other inflammatory mediators and mechanisms, such as central sensitization, are probably involved in the early stages of CRPS1.

Incidence rates and treatment of neuropathic pain conditions in the general population (Article)

2008-07-31T00:00:00Z

Incidence rate estimates of neuropathic pain are scanty and mostly address single types whereas the scope of the disease is wide. We aimed to calculate the incidence rates of neuropathic pain conditions in the Dutch general population and to assess treatment strategies in primary care. The study population included persons registered for at least one year in the Integrated Primary Care Information (IPCI) database between 1996 and 2003. Neuropathic pain was ascertained and classified by systematic review of computerized longitudinal medical records. Incidence rates (IR) were calculated, and the treatment for pain was compared to age and gender matched controls. Among 362,693 persons contributing 1,116,215 person years (PY), we identified 9135 new cases of neuropathic pain (IR: 8.2/1000 PY, 95%CI: 8.0-8.4). Mononeuropathy and carpal tunnel syndrome were the most frequent types with 4.3 and 2.3 cases/1000 PY followed by diabetic peripheral neuropathy and post-herpetic neuralgia at 0.72 and 0.42/1000 PY. Neuropathic pain was 63% more common in women than in men and peaked between the ages 70 and 79. More than 50% of cases received pain medication within 6 months after diagnosis, mostly consisting of NSAIDs or aspirin. Anticonvulsants and tricyclic antidepressants were only used by 4.8 and 4.7% of cases. Neuropathic pain is a rather frequent condition with an annual incidence of almost 1% of the general population and affecting women and middle-aged persons more often. The treatment mostly consisted of regular analgesics suggesting that pharmacological treatment of neuropathic pain is suboptimal.

Six years follow-up of the levels of TNF-α and IL-6 in patients with complex regional pain syndrome type 1 (Article)

2008-07-22T00:00:00Z

In an earlier study, levels of the proinflammatory cytokines TNF-α and IL-6 are higher in blisters fluid from the complex regional pain syndrome type 1 (CRPS1) side obtained at 6 and 30 months (median) after the initial event. The aim of this follow-up study is to determine the involvement of these cytokines in long lasting CRPS1. Twelve CRPS1 patients, with median disease duration of 72 months, participated. The levels of TNF-α and IL-6 were measured in blister fluid; disease activity was reevaluated by measuring pain and differences in temperature, volume, and mobility between both extremities. Differences in levels of IL-6 and TNF-α and mobility between both sides were significantly decreased. Pain and differences in temperature and volume were not significantly altered. No correlation was found between the cytokines and the disease characteristics. These results indicate that IL-6 and TNF-α are only partially responsible for the signs and symptoms of CRPS1. Copyright

Increased plasma serotonin in complex regional pain syndrome type 1 (Article)

2008-06-01T00:00:00Z

BACKGROUND: In patients with complex regional pain syndrome type 1 (CRPS1), some improvement can be achieved by the administration of ketanserin, a 5-HT2A receptor antagonist. We measured plasma levels of serotonin (5-HT) during CRPS1 and correlated these levels with disease characteristics. METHODS: Plasma 5-HT was measured in 35 patients who had CRPS1 for 3 yr and compared with 35 age-matched healthy controls. RESULTS: The plasma 5-HT levels were 411 ± 263 nmol/L and 29 ± 18 nmol/L, respectively (P < 0.001). No correlations with disease characteristics were observed. CONCLUSIONS: The markedly elevated levels of plasma 5-HT in CRPS1 patients suggest a role for 5-HT during the course of this disease. However, because of the lack of correlations with distinct disease characteristics, 5-HT is probably one of a number of mediators in CRPS1.

Increased plasma glutamate, glycine, and arginine levels in complex regional pain syndrome type 1 (Article)

2008-05-01T00:00:00Z

Background: Various inflammatory mediators have been identified as potential contributors to complex regional pain syndrome type 1 (CRPS1), but these mediators do not entirely explain certain manifestations of the syndrome, such as pain. The objective of this study was to investigate the role of amino acids in the pathogenesis of CRPS1. Methods: We used HPLC to determine plasma concentrations of 16 amino acids, especially those related to the NMDA receptor (e.g., glutamate and glycine) and nitric oxide (NO) synthesis (e.g., arginine and citrulline) in patients with CRPS1 (n=64) and age- and sex-matched healthy controls (n=51). Patients rated pain intensity (visual analog scale) and the subjective experience of pain intensity (McGill Pain Questionnaire). Psychological dysfunction was assessed using the SCL-90. Results: Relative to controls, in CRPS1 patients, plasma levels of glutamate, arginine, taurine, and glycine were increased, and plasma levels of glutamine and the ratio of citrulline to arginine were decreased. Remarkably, in CRPS1 patients there was a highly significant inverse correlation between glutamine and glutamate, although the sum of molar concentrations of glutamate and glutamine remains unchanged. Subjective measures of pain and indicators of psychoneuroticism and emotional instability did not correlate with amino acid levels. Conclusion: This study shows for the first time a pronounced increase in amino acid levels in this chronic pain syndrome. The marked differences in glutamate, glutamine, glycine, taurine and arginine levels between patients and controls suggest the involvement of both the NDMA receptor and the endothelium-dependent arginine-NO system in CRPS1.

Using skin surface temperature to differentiate between complex regional pain syndrome type 1 patients after a fracture and control patients with various complaints after a fracture (Article)

2008-01-01T00:00:00Z

OBJECTIVE: In this study, we assessed the validity of skin surface temperature recordings, based on various calculation methods applied to the thermographic data, to diagnose acute complex regional pain syndrome type 1 (CRPS1) fracture patients. METHODS: Thermographic recordings of the palmar/plantar side and dorsal side of both hands or feet were made on CRPS1 patients and in control fracture patients with/without and without complaints similar to CRPS1 (total in the three subgroups = 120) just after removal of plaster. Various calculation methods applied to the thermographic data were compared using receiver operating characteristics analysis to obtain indicators of diagnostic value. RESULTS: There were no significant differences in demographic data and characteristics among the three subgroups. The most pronounced differences among the subgroups were vasomotor signs in the CRPS1 patients. The involved side in CRPS1 patients was often warmer compared with the noninvolved extremity. The difference in temperature between the involved site and the noninvolved extremity in CRPS1 patients significantly differed from the difference in temperature between the contralateral extremities of the two control groups. The largest temperature difference between extremities was found in CRPS1 patients. The difference in temperature recordings comparing the palmar/plantar and dorsal recording was not significant in any group. The sensitivity and specificity varied considerably between the various calculation methods used to calculate temperature difference between extremities. The highest level of sensitivity was 71% and the highest specificity was 64%; the highest positive predictive value reached a value of 35% and the highest negative predictive 84%, with a moderate 0.60 ≥ area under the curve ≤ 0.65. CONCLUSION: The validity of skin surface temperature recordings under resting conditions to discriminate between acute CRPS1 fracture patients and control fracture patients with/without complaints is limited, and only useful as a supplementary diagnostic tool.

Vasodilative effect of isosorbide dinitrate ointment in complex regional pain syndrome type 1 (Article)

2008-01-01T00:00:00Z

BACKGROUND: In complex regional pain syndrome type 1 (CRPS1) vascular changes occur from the initial, inflammatory event onto the trophic signs during chronicity of the disease, resulting in blood flow disturbances and marked temperature changes. Pharmacotherapeutic treatment is generally inadequate. AIM: To determine whether local application of the nitric oxide donor isosorbide dinitrate (ISDN) could cause vasodilation and thereby improve tissue blood distribution in the affected extremity. METHODS: In a pilot study, 5 female patients with CRPS1 in one hand were treated with ISDN ointment 4 times daily during 10 weeks. As a primary objective videothermography was used to monitor changes in blood distribution in both the involved and contralateral extremities. RESULTS: Patients treated with ISDN showed an increase of 4°C to 6°C in mean skin temperature of the cold CRPS1 hands, reaching values similar to that of the contralateral extremities within 2 to 4 weeks time, suggesting normalization of blood distribution. This was confirmed by an improvement in skin color. In 3 patients the Visual Analog Scale pain declined, whereas in the other 2 patients the Visual Analog Scale pain was unchanged over time. CONCLUSIONS: In this pilot study, topical application of ISDN seems to be beneficial to improve symptoms for patients with cold type CRPS1, but further study is needed.

The incidence of complex regional pain syndrome: A population-based study (Article)

2007-05-01T00:00:00Z

The complex regional pain syndrome (CRPS) is a painful disorder that can occur in an extremity after any type of injury, or even spontaneously. Data on the incidence of CRPS are scarce and mostly hospital based. Therefore the size of the problem and its burden on health care and society are unknown. The objective of the present study was to estimate the incidence of CRPS in the general population. A retrospective cohort study was conducted during 1996-2005 in the Integrated Primary Care Information (IPCI) project, a general practice research database with electronic patient record data from 600,000 patients throughout the Netherlands. Potential CRPS cases were identified by a sensitive search algorithm including synonyms and abbreviations for CRPS. Subsequently, cases were validated by electronic record review, supplemented with original specialist letters and information from an enquiry of general practitioners. The estimated overall incidence rate of CRPS was 26.2 per 100,000 person years (95% CI: 23.0-29.7). Females were affected at least three times more often than males (ratio: 3.4). The highest incidence occurred in females in the age category of 61-70 years. The upper extremity was affected more frequently than the lower extremity and a fracture was the most common precipitating event (44%). The observed incidence rate of CRPS is more as four times higher than the incidence rate observed in the only other population-based study, performed in Olmsted County, USA. Postmenopausal woman appeared to be at the highest risk for the development of CRPS.

Nerve-identifying inguinal hernia repair: A surgical anatomical study (Article)

2007-02-01T00:00:00Z

Background: Pain syndromes of somatic and neuropathic origin are considered to be the main causes of chronic pain after open inguinal hernia repair. Nerve-identification during open hernia repair is suggested to be associated with less postoperative chronic pain. The aim of this study was to define clinically relevant surgical anatomical zones facilitating efficient identification of the three inguinal nerves during open herniorrhaphy. Method: Through dissection of 18 inguinal areas of embalmed and unembalmed human cadavers, identification zones were developed for the inguinal nerves (in particular for the genital branch of the genitofemoral nerve). Results: The iliohypogastric nerve was identifiable running approximately horizontally and ventrally to the internal oblique muscle perforating the external oblique aponeurosis at a mean of 3.8 cm (range 2.5-5.5 cm) cranially from the external ring. When present, the ilioinguinal nerve was identifiable running ventrally and parallel to the spermatic cord, dorsally from the aponeurosis of the external oblique muscle. Identification of the genital branch of the genitofemoral nerve was more comprehensive. The course of the genital branch is laterocaudal at the level of the internal inguinal ring. Conclusion: Based on the newly defined identification zones, peroperative identification of all inguinal nerves is possible. Further research is warranted to assess clinical feasibility of these zones and to evaluate the influence of (facultative) division, preservation or omittance of the identification of inguinal nerves on the incidence of chronic pain.

Thermography imaging during static and controlled thermoregulation in complex regional pain syndrome type 1: diagnostic value and involvement of the central sympathetic system. (Article)

2006-05-12T00:00:00Z

BACKGROUND: Complex Regional Pain Syndrome type 1 (CRPS1) is a clinical diagnosis based on criteria describing symptoms of the disease.The main aim of the present study was to compare the sensitivity and specificity of calculation methods used to assess thermographic images (infrared imaging) obtained during temperature provocation. The secondary objective was to obtain information about the involvement of the sympathetic system in CRPS1. METHODS: We studied 12 patients in whom CRPS1 was diagnosed according to the criteria of Bruehl. High and low whole body cooling and warming induced and reduced sympathetic vasoconstrictor activity. The degree of vasoconstrictor activity in both hands was monitored using a videothermograph. The sensitivity and specificity of the calculation methods used to assess the thermographic images were calculated. RESULTS: The temperature difference between the hands in the CRPS patients increases significantly when the sympathetic system is provoked. At both the maximum and minimum vasoconstriction no significant differences were found in fingertip temperatures between both hands. CONCLUSION: The majority of CRPS1 patients do not show maximal obtainable temperature differences between the involved and contralateral extremity at room temperature (static measurement). During cold and warm temperature challenges this temperature difference increases significantly. As a result a higher sensitivity and specificity could be achieved in the diagnosis of CRPS1. These findings suggest that the sympathetic efferent system is involved in CRPS1.

Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. (Article)

2006-03-31T00:00:00Z

Inflammatory processes are known to be involved at least in the early phase of complex regional pain syndrome type 1 (CRPS1). Blister fluid obtained from the involved extremities displayed increased amounts of proinflammatory cytokines IL-6 and TNFalpha compared with the noninvolved extremities. The aim of this paper is to investigate the involvement of mediators by measurement of several other cytokines using new detection techniques that enable multiple cytokine measurement in small samples. The use of a multiplex-25 bead array cytokine assay and Luminex technology enabled simultaneous measurement of representative (1) proinflammatory cytokines such as GM-CSF, IL-1beta, IL-1RA, IL-6, IL-8, and TNF-alpha; (2) Th1/Th2 distinguishing cytokines IFN-gamma, IL-2, IL-2R, IL-4, IL-5, and IL-10; (3) nonspecific acting cytokines IFN-alpha, IL-7, IL-12p40/p70, IL-13, IL-15, and IL-17; and (4) chemokines eotaxin, IP-10, MCP-1, MIP-1alpha, MIP-1beta, MIG, and RANTES. Although minimal detection levels are significantly higher in the bead array system than those in common ELISA assays, in blister fluid, IL-1RA, IL-6, IL-8, TNF-alpha, IL-12p40/p70, MCP-1, and MIP-1beta were detectable and increased in CRPS1 affected extremities. Levels of IL-6 and TNF-alpha simultaneously measured by ELISA (Sanquin Compact kit) and by multiplex-25 bead array assay (Biosource) were highly correlated (r = 0.85, P < .001 for IL-6 and r = 0.88, P < .001 for TNF-alpha). Furthermore, IP-10 and eotaxin were detectable but diminished in CRPS1, whereas detectable amounts of IL-10 were similar in involved and noninvolved extremities. Multiplex bead array assays are useful systems to establish the involvement of cytokines in inflammatory processes by measurements in blister fluids of CRPS1. Ten representative cytokines were detectable. However, detection levels and amounts measured are at least 3 times higher in the multiplex-25 array assay than in the ELISA assays used simultaneously for the measurement of cytokines.

Intermediate stage complex regional pain syndrome type 1 is unrelated to proinflammatory cytokines. (Article)

2005-12-14T00:00:00Z

The aim of this paper is to determine the involvement of tumour necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in intermediate CRPS 1 as locally formed mediators of inflammation. In this study, 25 patients with proven CRPS 1 (Bruehl criteria) were included. All patients participated in one of our earlier studies during the acute stage of their disease. After the disease developed into an intermediate stage, both the disease activity and the profile of inflammatory mediators were reevaluated. Disease activity and impairment were determined by means of a visual analogue scale, the McGill Pain Questionnaire, the difference in volume and temperature between the involved and uninvolved extremities, and the reduction in active range of motion of the involved extremity. Suction blisters were made on the involved and uninvolved extremities for measurement of IL-6 and TNF-alpha. A significant improvement in signs and symptoms of impairment was found. However, the levels of IL-6 and TNF-alpha in blister fluid in the involved extremity versus uninvolved extremity were still significantly raised. Although signs and symptoms are significantly improved, proinflammatory cytokines are still increased in CRPS 1 affected extremities during the intermediate stage of the disease. This indicates that the initiation and sustained development of the disease are only partially affected by proinflammatory cytokines. Follow-up in the chronic stage is necessary to draw more definite conclusions about the existence of a supposed relation between clinical signs and symptoms and the level of proinflammatory cytokines.

Neuroimmune Alterations in the Complex Regional Pain Syndrome (Doctoral Thesis)

2004-07-02T00:00:00Z

Complex Regional Pain Syndrome (CRPS) is a disease which occurs as a complication after surgery or trauma, although spontaneous development is described. CRPS is characterized by continuing pain, sensory and vasomotor, sudomotor, motor and trophic disturbances. Many of these symptoms are normal during a period of recovery after surgery or trauma and are part of a sterile infl ammatory process and disuse. This is the process which normally leads to restoration. Characteristic for CRPS is that this reaction does not seem to stop, the normal sterile infl ammatory process seems to continue. This clinical picture is often combined with disturbances of the central nervous system including allodynia, sympathetic dysregulation and dystonia. A difference is made between CRPS type 1 (CRPS 1), without nerve damage and CRPS type 2 (CRPS 2), with nerve damage.