Low-Dose Intravenous Immunoglobulin Treatment for Long-Standing Complex Regional Pain Syndrome: A Randomized Trial.

BACKGROUND: Two small trials suggest that low-dose intravenous immunoglobulin (IVIg) may improve the symptoms of complex regional pain syndrome (CRPS), a rare posttraumatic pain condition. OBJECTIVE: To confirm the efficacy of low-dose IVIg compared with placebo in reducing pain during a 6-week period in adult patients who had CRPS from 1 to 5 years. DESIGN: 1:1 parallel, randomized, placebo-controlled, multicenter trial for 6 weeks, with an optional 6-week open extension. Patients were randomly assigned to 1 of 2 study groups between 27 August 2013 and 28 October 2015; the last patient completed follow-up on 21 March 2016. Patients, providers, researchers, and outcome assessors were blinded to treatment assignment. (ISRCTN42179756). SETTING: 7 secondary and tertiary care pain management centers in the United Kingdom. PARTICIPANTS: 111 patients with moderate or severe CRPS of 1 to 5 years' duration. INTERVENTION: IVIg, 0.5 g/kg of body weight, or visually indistinguishable placebo of 0.1% albumin in saline on days 1 and 22 after randomization. MEASUREMENTS: The primary outcome was 24-hour average pain intensity, measured daily between days 6 and 42, on an 11-point (0- to 10-point) rating scale. Secondary outcomes were pain interference and quality of life. RESULTS: The primary analysis sample consisted of 108 eligible patients, 103 of whom had outcome data. Mean (average) pain scores were 6.9 points (SD, 1.5) for placebo and 7.2 points (SD, 1.3) for IVIg. The adjusted difference in means was 0.27 (95% CI, -0.25 to 0.80; P = 0.30), which excluded the prespecified, clinically important difference of -1.2. No statistically significant differences in secondary outcomes were found between the groups. In the open extension, 12 of the 67 patients (18%) who received 2 IVIg infusions had pain reduction of at least 2 points compared with their baseline score. Two patients in the blinded phase (1 in the placebo and 1 in the IVIg group) and 4 in the open IVIg phase had serious events. LIMITATIONS: Results do not apply to patients who have had CRPS for less than 1 year or more than 5 years and do not extend to full-dose treatment (for example, 2 g/kg). The study was inadequately powered to detect subgroup effects. CONCLUSION: Low-dose immunoglobulin treatment for 6 weeks was not effective in relieving pain in patients with moderate to severe CRPS of 1 to 5 years' duration. PRIMARY FUNDING SOURCE: Medical Research Council/National Institute for Health Research Efficacy and Mechanism Evaluation Program, Pain Relief Foundation, and Biotest United Kingdom.

Improving pain control in diabetic neuropathy.

Diabetic neuropathy is thought to affect 1.9% of the world's population and 50% of patients with a diagnosis of diabetes mellitus which would equate to 2.25 million people in the UK. The term diabetic neuropathy includes multiple distinct clinical entities that have been classified under the broad headings of focal and multifocal neuropathies and symmetrical neuropathies. Peripheral diabetic neuropathy, a chronic distal symmetrical predominantly sensory neuropathy, is the most common form of diabetic neuropathy. Most patients describe moderate to severe pain, using neuropathic descriptors such as burning, shooting or electric shocks. The common presentation is of painful symptoms originating in the feet, that then spread to the knees before involving the distal portion of the upper limbs in a 'glove and stocking' distribution. There are number of specific neuropathic pain assessment tools that can be readily used in a non-specialist setting in the community, such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) questionnaire. This combines five simple questions and two examination findings to give a dimensionless score for the pain out of 24, with a score ≥ 12 suggesting a neuropathic component is likely.

Controlling joint pain in older people.

Jont pain in oldder people The prevalence of chronic pain in older people in the community ranges from 25 to 76% and for those in residential care, it is even higher at 83 to 93%. The most common sites affected are the back, hip, or knee, and other joints. There is increased reporting of pain in women (79%) compared with men (53%). Common conditions include osteoarthritis and, to a lesser extent, the inflammatory arthropathies such as rheumatoid arthritis. The differential diagnosis includes non-articular pain such as vascular limb pain and nocturnal cramp, some neuropathic pain conditions (such as compressive neuropathies and postherpetic neuralgia), soft tissue disorders such as fibromyalgia and myofascial pain syndromes. In addition to an assessment of pain intensity, a biopsychosocial model should be adopted to ascertain the effect of the pain on the patient's degree of background pain at rest. The disease is often localised to the large load-bearing joints, predominantly the hips and knees. In contrast to osteoarthritis, the inflammatory arthritides typically present with symmetrical swollen, stiff, and painful small joints of the hands and feet, usually worse in the morning.

Tailor treatment to the patient with neuropathic pain.

Neuropathic pain can be considered to be a clinical syndrome with multiple causes ranging from damage to peripheral nerve pathways as the level of peripheral nociceptors to abnormalities in the cortical neurons in the brain. It is defined as pain that is caused by a lesion or disease of the somatosensory nervous system and is estimated to affect 6-8% of the general population. A low threshold of suspicion in conditions associates with neuropathic pain can aid diagnosis. Data from the past decade suggest that it is found in 16-26% of patients with diabetes, 8% of patients suffering from shingles in the past three months (increasing to 40% and 75% in patients aged over 50 and 75 respectively), and 10-50% of patients following surgery. Typical neuropathic descriptors include burning, shooting electric shock pain with numbness, pins and needles or itching. After general and neurological examination the focus should turn to the affected pain area using an unaffected body part as a control. Sensory response to cotton wool, pinprick, temperature and vibration should all be assessed. This will identify the positive and negative signs found in neuropathic pain. Tinel's sign and Phalen's sign, although classically taught, have such poor sensitivity and specificity that GPs are no longer encouraged to rely on them, and they should not be used. Neuropathic pain is often poorly responsive to conventional analgesia with the mainstay of treatment being anticonvulsant and antidepressant medication. Multidisciplinary assessment and management in the specialist setting of the pain clinic is often requires.

Burden of herpes zoster in the UK: findings from the zoster quality of life (ZQOL) study.

BACKGROUND: Herpes zoster (HZ) is a painful condition that can have a substantial negative impact on patients' lives. However, UK-specific data on the debilitating impact of HZ, in terms of patients' experience of pain and impairments in Health-Related Quality of Life (HRQoL) are limited. The Zoster Quality of Life (ZQOL) study, a large-scale UK cross-sectional study, was conducted to quantify the burden of HZ in UK patients. METHODS: A total of 229 HZ patients aged 50 years or over were recruited from primary and secondary/tertiary care centres throughout the UK. Patients completed a battery of validated questionnaires, including the Zoster Brief Pain Inventory (ZBPI), the Medical Outcomes Study Short-Form 36 (SF-36) and the EuroQol-5 Dimensions (EQ-5D) on initial presentation to the doctor and again 7-14 days later. At follow-up patients also completed the Treatment Satisfaction with Medication (TSQM) questionnaire. Where available, mean questionnaire scores in the HZ population were compared to scores for age-matched norms to investigate the burden associated with HZ. RESULTS: Pain was prominent among patients, with 57.9% at the initial study visit reporting pain in the preceding 24 hours at levels typically considered to have a significant impact on HRQoL (i.e. ZBPI worst pain ≥ 5). This was reflected in SF-36 and EQ-5D scores that were significantly lower for patients when compared to age-matched norms (p < 0.05) - except for the SF-36 domain of physical functioning. HRQoL was inversely associated with levels of reported pain, with those patients in the greatest amount of pain reporting the greatest HRQoL impact. However, there was no association between pain severity and participant age. The majority of patients (69.4%) received antivirals within 72 hours of rash appearing and 69.9% of patients were also taking analgesics for the management of HZ pain. TSQM scores indicated that patients were least satisfied with the effectiveness of their prescribed treatment. CONCLUSIONS: The acute presentation of HZ is a painful experience that can have a significant impact on the physical and mental wellbeing of sufferers. Findings highlight significant unmet need among patients, particularly in terms of the effectiveness of therapies for the management of HZ.

Burden of post-herpetic neuralgia in a sample of UK residents aged 50 years or older: findings from the Zoster Quality of Life (ZQOL) study.

BACKGROUND: Post-herpetic neuralgia (PHN) is the most common complication of herpes zoster (shingles). As a chronic condition, PHN can have a substantial adverse impact on patients' lives. However, UK-specific data concerning the burden of PHN on individual patients, healthcare systems and wider society, are lacking. As the first UK-wide cross-sectional study of its kind, The Zoster Quality of Life (ZQOL) study was designed to address these concerns. METHODS: Patients (n = 152) with a confirmed diagnosis of PHN (defined as pain persisting ≥ 3 months following rash onset) and aged ≥50 years were recruited from primary and secondary/tertiary care centres throughout the UK. All patients completed validated questionnaires, including the Zoster Brief Pain Inventory (ZBPI), the Medical Outcomes Study Short-Form 36 (SF-36), the EuroQol-5 Dimensions (EQ-5D) and the Treatment Satisfaction with Medication (TSQM) questionnaire. Where available, mean patient population scores on these questionnaires were compared to scores derived from age-matched normative samples to quantify the burden associated with PHN. RESULTS: Despite numerous consultations with healthcare professionals and receiving multiple medications for the management of their PHN, the majority of patients reported being in pain 'most of the time' or 'all of the time'. A total of 59.9% (n = 91) of all PHN patients reported pain in the preceding 24 hours to assessment at levels (ZBPI worst pain ≥ 5) typically considered to have a significant impact on Health Related Quality of Life (HRQoL). Accordingly, scores for SF-36 and EQ-5D indicated significant deficits in HRQoL among PHN patients compared to age-matched norms (p < 0.05) and patients reported being dissatisfied with the perceived efficacy of therapies received for the management of PHN. Increased pain severity was observed among older participants and higher levels of pain severity were associated with greater HRQoL deficits. CONCLUSIONS: The inadequate relief provided by PHN therapies available in the UK is associated with a significant burden among PHN patients in terms of pain severity and deficits in HRQoL which may persist for years. Therefore, alternative means such as prevention of shingles and PHN, are essential for reducing the impact on individual patients, healthcare systems and society as a whole.

Improving outcomes for chronic pain in primary care.

Although the patient's goal is often complete pain relief, this is rarely a realistic outcome, so the role of the physician in managing chronic pain involves optimising pain relief as far as possible. Careful explanation and education may be needed to enable the focus to shift from cure to better management of pain, and improvement of function and quality of life. Chronic pain is defined as pain continuing beyond the normal time for tissue healing. Pain may be broadly classified on the basis of mechanism, as neuropathic, nociceptive or mixed. A thorough biopsychosocial assessment is essential so that an individualised multidisciplinary approach to management can be developed. The aims of assessment of chronic pain are to rule out any underlying serious pathology, identify the pain mechanism and identify and evaluate risk factors that contribute to chronicity. SIGN emphasises the need for a multidisciplinary team approach to improve outcomes, and highlights five broad categories of care: supported self-management, drug treatment, psychologically-based interventions, physical therapies and complementary therapies. Exercise, regardless of its type and the source of pain, is recommended for the management of chronic pain. In chronic low back pain, exercise therapy can improve strength and range of motion across joints, cardiorespiratory fitness and sense of wellbeing. Pain management programmes reduce anxiety and depressive symptoms, increase function and improve mood. They may be considered in patients with poor functional capacity, pain-related social and occupational problems and in cases where other management strategies have failed.

Pain resulting from arteriovenous fistulae: prevalence and impact.

INTRODUCTION: The burden of pain from cannulation of arteriovenous fistulae (AVF) and the impact it has on quality of life is poorly described in the literature. METHODOLOGY: A pain score questionnaire was employed for all patients in the West of Scotland dialyzing via AVF (n = 461). Pain was assessed using visual analogue score (VAS) and McGill pain score. Patients with severe pain (VAS > 5) were compared to those with minimal pain. RESULTS: The questionnaire as completed by 97.5% of the patients. Median VAS on cannulation was 3 (IQR 0.5 - 4.5). Of those who had completed the questionnaire, 24.4% had severe pain on cannulation and 3.2% experienced severe chronic pain. 53 patients (11.3%) cut a dialysis session short due to pain. Of the patients with severe chronic pain, 46.7% had a physical complication affecting their AVF (e.g., venous stenosis, pseudoaneurysm). Following treatment of the problem, pain improved in 71.4% and resolved completely in 14.3%. Brachiobasilic AVF was associated with a higher incidence of severe pain than either brachiocephalic or radiocephalic AVF (50%, 23.3% and 24.4% respectively; p = 0.03). There was a trend towards more severe pain with rope-ladder cannulation (27.7%) compared to button-hole cannulation (18.2%); however, this difference did not reach statistical significance (p = 0.09). CONCLUSIONS: Pain from AVF is poorly recognized and an under-reported problem. While severe pain resulting in the avoidance of dialysis is rare, it can lead to significant difficulties and ultimate abandonment of AVF. Pain is often suggestive of an underlying anatomical problem.

The relevance of real-world data for the evaluation of neuropathic pain treatments.

Treatment of neuropathic pain (NP) is challenging. Interest in real-world evidence (RWE) for benefit-risk assessments of NP treatments increases given the paucity of drugs showing efficacy in randomized controlled trials and restricted labels of available medicines. To provide further context, a literature review regarding regulatory use of RWE and a clinical trial registry search for randomized controlled trials over the last 10 years was carried out. Taken together, and especially for available NP treatments, there is increasing support to consider RWE when evaluating their benefit-risk profile. Examples are provided in which RWE could be used effectively for updating the product label and informing treatment recommendations. Collected and analyzed according to state-of-the-art standards, RWE can inform treatment recommendations and product label decisions.

Neuropathic pain (NP) is caused by damage to the sensory part of the nervous system and is often described as burning, throbbing or shooting pain. This condition is difficult to treat and may become chronic. Before a new treatment can be approved for use, its effectiveness and safety must be shown in controlled clinical trials. Such trials are difficult to conduct in NP and often fail. Therefore, there is increasing support for the use of real-world data (routinely collected data from e.g., patient registries, electronic medical records, health insurance claims databases) to evaluate the benefits and risks of treatments. This article presents the views of three pain specialists about the value of real-word evidence in general and specifically for the evaluation of pharmacological treatments of NP.

Localised neuropathic pain in the primary care setting: a cross-sectional study of prevalence, clinical characteristics, treatment patterns, quality of life and sleep performance.

BACKGROUND: Localised Neuropathic Pain (LNP) is challenging to diagnose and manage in primary care. OBJECTIVE: To describe clinical characteristics, treatment patterns, quality of life and sleep performance of patients with LNP and estimate its prevalence in primary care. METHODS: Cross-sectional study in 4 European countries. Patients were identified using a screening tool for LNP. Patients completed the EQ-5D VAS score and Chronic Pain Sleep Inventory (CPSI). RESULTS: There were 1030 LNP patients for analysis. They presented a median pain intensity of 6.0 (IQR 4.0-7.0) with a median duration of 30.9 months (IQR 12.0-75.3), despite 97% receiving pain treatment. Main sites affected were the limbs (62% upper/58% lower) and spine (41%). Main aetiologies were neuropathic low back pain (47%), post-surgical neuropathic pain (17%), and diabetic poly-neuropathy (12%). Thirty percent received a single analgesic (2% topical), while combinations comprised 43% systemic-systemic, 24% topical-systemic, 1% topical-topical. Medications included NSAIDs (45%), anticonvulsants (38%), WHO step 2 opioids (35%), and topical analgesics (27%). In the previous 6 months, 40% had switched treatment. The mean (SD) EQ-5D VAS score was 58 (22.3) and the mean (SD) EQ-5D summary score (UK tariff) was 0.62 (0.25). Patients had a CPSI mean index of 41/100, and sleeping pills were used by 33% of patients. The standardized prevalence of LNP by age and sex was 2.01% in the general population and 43.3% among chronic pain patients. CONCLUSIONS: Many LNP patients reported pain intensities of six on a ten-point scale in average for durations longer than 2.5 years, with quality of life and sleep performance affected, with frequent treatment combinations and switches, suggesting suboptimal pain management.

Successful and unsuccessful recruitment and retainment strategies in a UK multicentre drug trial for a rare chronic pain condition which performed above target.

INTRODUCTION: Recruitment into trials in rare chronic pain conditions can be challenging, so such trials consequently are underpowered or fail. METHODS: Drawing from our experience in conducting, to date, the largest academic trial in a rare chronic pain condition, complex regional pain syndrome, we have identified recruitment and retention strategies for successful trial conduct. RESULTS: We present 13 strategies grouped across the categories of 'setting the recruitment rate', 'networking', 'patient information', 'trial management' and 'patient retention'. Moreover, six recruitment risks are also discussed. A conservative recruitment estimate, based on audits of newly referred patients to the trial centres without taking into account availability of 'old' patients or recruitment from outside centres, and assuming a 55% patient refusal rate yielded accurate numbers. CONCLUSION: Appreciation of these identified recruitment challenges and opportunities may contribute to supporting prospective investigators when they design clinical trials for chronic pain patient population groups where it has been historically difficult to conduct high-quality and robust clinical trials.

Assessment of Transdermal Buprenorphine Patches for the Treatment of Chronic Pain in a UK Observational Study.

BACKGROUND: Opioids provide effective analgesia for moderate-to-severe, chronic pain. Transdermal buprenorphine (TDB) is available in the UK as weekly, lower-dose (5-20 µg/h) patches and twice-weekly, higher dose (35-70 µg/h) patches. This prospective, observational, multicenter study of patients with various chronic pain conditions assessed the safety, perceptions, and discontinuation of treatment with TDB in a real-world, non-interventional setting (ClinicalTrials.gov study ID: NCT01225861). METHODS: Patients aged ≥18 years who were already receiving or initiating treatment with TDB were recruited in the UK during routine clinical visits and were followed for 6 visits or 9 months (whichever came first). Self-reported treatment adherence, patient satisfaction, and safety data were collected at each study visit. RESULTS: Of 465 patients, 272 were already receiving 7-day TDB at the study start (TDB experienced), 146 were TDB naïve, and 47 were prescribed twice-weekly TDB. Most patients were female (72.9 %) and overweight/obese (body mass index ≥25: 75.3 %). The median age was 67 years, and the mean duration of pain was 11.1 years. Arthritis/other musculoskeletal disorders (39.6 %) were the most common causes of pain. Mild adverse events were commonly reported. Skin irritations, which were most frequent in 7-day TDB-experienced patients (45.6 %), rarely resulted in treatment discontinuation (8.8 %). Nearly all patients used TDB in accordance with treatment recommendations. Most patients reported that TDB was 'effective'/'very effective' at relieving pain and were 'satisfied'/'very satisfied' with TDB therapy. CONCLUSION: In everyday clinical practice, TDB was well tolerated and patients were satisfied with their therapy. Self-reported adherence to TDB was very high, and adverse events rarely resulted in treatment discontinuation. Opportunities were identified to limit common adverse events associated with TDB.

Low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS): study protocol for a randomized controlled trial.

BACKGROUND: Longstanding complex regional pain syndrome (CRPS) is refractory to treatment with established analgesic drugs in most cases, and for many patients, alternative pain treatment approaches, such as with neuromodulation devices or rehabilitation methods, also do not work. The development of novel, effective treatment technologies is, therefore, important. There are preliminary data suggesting that low-dose immunoglobulin treatment may significantly reduce pain from longstanding CRPS. METHODS/DESIGN: LIPS is a multicentre (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. Participants with moderate or severe CRPS of between 1 and 5 years duration will be randomly allocated to receive IVIg 0.5 g/kg (IntratectTM 50 g/l solution for infusion) or matching placebo administered day 1 and day 22 after randomisation, followed by two optional doses of open-label medication on day 43 after randomisation and on day 64 after randomisation. The primary outcome is the patients' pain intensity in the IVIG group compared with the placebo group, between 6 and 42 days after randomisation. The primary trial objective is to confirm the efficacy and confidently determine the effect size of the IVIG treatment technology in this group of patients. TRIAL REGISTRATION: ISRCTN42179756 (Registered 28 June 13).

Chronic pain following donor nephrectomy--a study of the incidence, nature and impact of chronic post-nephrectomy pain.

Chronic pain is a consequence of some types of surgery, but its incidence following open donor nephrectomy has never been investigated. We surveyed 123 patients who underwent open donor nephrectomy at our institution over a 10-year period, to determine the incidence, severity and nature of chronic pain and its effect on quality of life. Of the 81 (66%) responders, 27 (33%) had experienced prolonged pain, and 21 (26%) still had chronic pain related to their surgery. The overall incidence of severe, disabling pain (visual analogue score 7) was 12% and of neuropathic pain was 14%. The average loss in quality adjusted life years (QALYs) was 1.053 for chronic pain sufferers, but was 1.851 for those who suffered specifically from neuropathic pain. Only one third of patients with chronic pain were receiving any treatment, and none were receiving neuropathic adjuvants or specialist pain management interventions. We conclude that the incidence of chronic pain following donor nephrectomy is underestimated and therefore under managed. Given the voluntary and altruistic nature of this procedure, and the enormous personal and social benefits which result from successful donor transplantation, those involved with the preparation and post-operative management should be more aware of, and actively question donors about chronic pain so that diagnosis and appropriate therapy can be commenced as early as possible.

Diagnosis and assessment of neuropathic pain.

Neuropathic pain and pain that has a predominant neuropathic component can be difficult to diagnose in primary care. Several screening questionnaires that incorporate patient symptoms and signs have been developed, and some are supplemented with simple bedside clinical tests for nerve dysfunction. These tools should enable a more rapid and confident diagnosis by the nonspecialist and the earlier start of appropriate treatment.

Sativex successfully treats neuropathic pain characterised by allodynia: a randomised, double-blind, placebo-controlled clinical trial.

Cannabinoids are known to have analgesic properties. We evaluated the effect of oro-mucosal sativex, (THC: CBD), an endocannabinoid system modulator, on pain and allodynia, in 125 patients with neuropathic pain of peripheral origin in a five-week, randomised, double-blind, placebo-controlled, parallel design trial. Patients remained on their existing stable analgesia. A self-titrating regimen was used to optimise drug administration. Sixty-three patients were randomised to receive sativex and 62 placebo. The mean reduction in pain intensity scores (primary outcome measure) was greater in patients receiving sativex than placebo (mean adjusted scores -1.48 points vs. -0.52 points on a 0-10 Numerical Rating Scale (p=0.004; 95% CI: -1.59, -0.32). Improvements in Neuropathic Pain Scale composite score (p=0.007), sleep NRS (p=0.001), dynamic allodynia (p=0.042), punctate allodynia (p=0.021), Pain Disability Index (p=0.003) and Patient's Global Impression of Change (p<0.001) were similarly greater on sativex vs. placebo. Sedative and gastrointestinal side effects were reported more commonly by patients on active medication. Of all participants, 18% on sativex and 3% on placebo withdrew during the study. An open-label extension study showed that the initial pain relief was maintained without dose escalation or toxicity for 52 weeks.