Pain sensitisation and the risk of poor outcome following physiotherapy for patients with moderate to severe knee osteoarthritis: protocol for a prospective cohort study Has postoperative pain been eradicated? Characterisation of capsaicin-induced mechanical hyperalgesia as a marker for altered nociceptive processing in patients with rheumatoid arthritis A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation
Introduction Pain is the dominant symptom of knee osteoarthritis ( OA ) , and recent evidence suggests factors outside of local joint pathology , such as pain sensitisation , can contribute significantly to the pain experience . It is unknown how pain sensitisation influences outcomes from commonly employed interventions such as physiotherapy . The aims of this study are , first , to provide a comprehensive description of the somatosensory characteristics of people with pain associated with knee OA . Second , we will investigate if indicators of pain sensitisation in patients with knee osteoarthritis are predictive of non-response to physiotherapy . Methods and analysis This is a multicentre prospect i ve cohort study with 140 participants . Eligible patients with moderate to severe symptomatic knee osteoarthritis will be identified at outpatient orthopaedic and rheumatology clinics . A baseline assessment will provide a comprehensive description of the somatosensory characteristics of each participant by means of clinical examination , quantitative sensory testing , and vali date d question naires measuring pain and functional capacity . Participants will then undergo physiotherapy treatment . The primary outcome will be non-response to physiotherapy on completion of the physiotherapy treatment programme as defined by the Osteoarthritis Research Society International treatment responder criteria . A principal component analysis will identify measures related to pain sensitisation to include in the predictive model . Regression analyses will explore the relationship between responder status and pain sensitisation while accounting for confounders . Ethics and dissemination This study has been approved by St James ’ Hospital/AMNCH Research Ethics Committee and by the St Vincent 's Healthcare Group Ethics and Medical Research Committee . The results will be presented at international conferences and published in a peer review journal . Trial registration number NCT02310945 Recent evidence suggests that surgical trauma induces a process of central nervous system sensitisation that contributes to and enhances postoperative pain . These changes are also thought to be the underlying cause of much chronic pain . Central sensitisation is generated not only during surgery , but also postoperatively as a result of the inflammatory response to the damaged tissue . This knowledge provides a rational basis for pro-active , pre-emptive and postoperative analgesic strategies to reduce the neuronal barrage associated with tissue damage . Reduction or elimination of postoperative pain is therefore possible . We advocate the use of continuous extrapleural intercostal nerve block for postoperative analgesia in patients undergoing thoracotomy .  When this is begun pre-emptively ( by precutaneous , pre-incisional paravertebral block ) it is combined with an opiate and a non-steroidal anti-inflammatory drug premedication . In a r and omised study of 56 patients , pain scores of less than 0.5 cm on a 10 cm scale were produced , postoperative lung function was preserved and glucose and cortisol responses were significantly unchanged from preoperative values . Evidence that effective perioperative analgesia reduces the incidence of chronic post-thoracotomy chest wall pain was found in a retrospective study of 1000 consecutive thoracotomies . The endpoints of a zero pain score , complete preservation of preoperative lung function and prevention of the stress response to trauma are currently achievable and should be provided for virtually all patients undergoing chest surgery . Pre-empting pain must be the goal for all those involved in the postoperative care of patients Abstract Rheumatoid arthritis ( RA ) is characterised by pain and tenderness not only over inflamed or damaged joints , but also over apparently normal tissues . Experimental models suggest that these features result from changes of sensitivity within both peripheral and central neurones , but direct evidence from human disease is lacking . At present , most clinical studies have evaluated overall pain experience rather than activity within components of the nociceptive pathway . Therefore , the aim of this study was to assess the use of a capsaicin‐based technique to quantify changes of neuronal sensitivity in patients with RA . First 20 & mgr;l of capsaicin in solution ( 0.03 mg/ml ) was applied topically for 30 min to apparently normal skin on the forearm of control subjects and patients with RA . The subsequent development of mechanical hyperalgesia to pinprick stimuli was then measured at various time points using a 74.4‐mN von Frey hair . The relationship between the area of hyperalgesia and a number of clinical measures was determined .  Capsaicin‐induced mechanical hyperalgesia was found to decline with age in normal subjects ( r=0.47 , P<0.01 ) . The development of hyperalgesia had a similar time course in normal subjects and patients with RA .  The maximum area of hyperalgesia , however , was substantially larger in 35 RA patients ; 254.3±20.7 cm2 , compared with 35 normal controls ; 109±7.5 cm2 ( P<0.001 ) . An association was apparent between hyperalgesic area and a composite score of joint tenderness ( r=0.47 , P<0.01 ) , but not with overall pain score or a systemic marker of inflammation . These results provide evidence for enhanced sensitisation of a population of sensory fibres in RA . Peripheral sensory activity over the forearms of rheumatoid patients has previously been shown to be normal and the results suggest the presence of enhanced central mechanisms in this disorder . The correlation between  capsaicin‐induced hyperalgesia and joint tenderness in the RA patients implies that joint symptoms arise partially as a result of central , and not exclusively peripheral , factors . The study supports the use of capsaicin‐based techniques to explore nociceptive mechanisms in clinical disorders characterised by chronic pain & NA ; Persistent pain has been reported in up to 80 % of patients after limb amputation . The mechanisms are not fully understood , but nerve injury during amputation is important , with evidence for the crucial involvement of the spinal N‐methyl d‐aspartate ( NMDA ) receptor in central changes . The study objective was to assess the effect of pre‐emptively modulating sensory input with epidural ketamine ( an NMDA antagonist ) on post‐amputation pain and sensory processing . The study recruited 53 patients undergoing lower limb amputation who received a combined intrathecal/epidural anaesthetic for surgery followed by a r and omised epidural infusion ( Group K received racemic ketamine and bupivacaine ; Group S received saline and bupivacaine ) . Neither general anaesthesia nor opioids were used during the peri‐operative period . Pain characteristics were assessed for 12 months . The primary endpoint was incidence and severity of post‐amputation pain . Persistent pain at one year was much less in both groups than in comparable studies , with no significant difference between groups ( Group K = 21 % ( 3/14 ) and 50 % ( 7/14 ) ; and Group S = 33 % ( 5/15 ) and 40 % ( 6/15 ) for stump and phantom pain , respectively ) . Post‐operative analgesia was significantly better in Group K , with reduced stump sensitivity . The intrathecal/epidural technique used , with peri‐operative sensory attenuation , may have reduced ongoing sensitisation , reducing the overall incidence of persistent pain . The improved short‐term analgesia and reduced mechanical sensitivity in Group K may reflect acute effects of ketamine on central sensitisation . Longer term effects on mood were detected in Group K that requires further study
Results There is good evidence for a role of central sensitisation in chronic OA pain in a subgroup of patients .
Biomarkers may be helpful for confirming the presence of central sensitisation , especially when there is diagnostic uncertainty .
Several non‐pharmacological and pharmacological treatments may be effective in OA patients with central sensitisation features .
Multimodal therapy may be required to achieve control of symptoms .
Summary Aims The aim of this non‐ systematic review was to provide a practical guide for clinicians on the evidence for central sensitisation in chronic osteoarthritis ( OA ) pain and how this pain mechanism can be addressed in terms of clinical diagnosis , investigation and treatment .
Clinical ly , a central sensitisation component in chronic OA pain can be suspected based on characteristic pain features and non‐pain features seen in other conditions involving central sensitisation .