Spinal cord stimulation (SCS) is a recommended treatment for chronicrefractory neuropathic pain. During the COVID-19 pandemic, electiveprocedures have been postponed indefinitely both to provide capacity to dealwith the emergency caseload and to avoid exposure of elective patients toCOVID-19. This survey aimed to explore the effect of the pandemic on chronicpain in this group and the views of patients towards undergoing SCStreatment when routine services should resume.This was a prospective, multi-centre telephone patient survey that analyseddata from 330 patients with chronic pain who were on an SCS waiting list.Questions focussed on severity of pain, effect on mental health, medicationconsumption and reliance on support networks during the COVID-19 pandemic.Views towards undergoing SCS therapy were also ascertained. Counts andpercentages were generated, and chi-square tests of independence exploredthe impact of COVID-19 risk  on survey responses.Pain, mental health and patient’s ability to self-manage pain deteriorated inaround 47%, 50% and 38% of patients, respectively. Some patients reportedincreases in pain medication consumption (37%) and reliance on supportnetwork (41%). Patients showed a willingness to attend for COVID-19 testing(92%), self-isolate prior to SCS (94%) and undergo the procedure as soon aspossible (76%).Our findings suggest that even during the COVID-19 pandemic, there remains astrong clinical need for patients with chronic pain identified as likely SCSresponders to be treated quickly. The current prioritisation of new SCS atcategory 4 (delayed more than 3 months) is challenged judging by thisnational survey. These patients are awaiting SCS surgery to relieve severeintractable neuropathic pain. A priority at category 3 (delayed up to3 months) or in some selected cases, at category 2 are the appropriatepriority categories. In late December 2019, a new strain of coronavirus, later called COVID-19, wasidentified in Wuhan, China. By 30 January 2020, COVID-19 was classed as a publichealth emergency of international concern (PHEIC) by the World Health Organizationand declared a pandemic on 11 March 2020. Currently recognised symptoms of COVID-19include fever, cough, anosmia and shortness of breath and, in severe cases,breathing difficulties which can require mechanical ventilation. Complications ofCOVID-19 have been reported to include pneumonia, adult respiratory distresssyndrome, cytokine storm and sepsis. In the United Kingdom, COVID-19 has had profound effects on National HealthService (NHS) services, particularly following the country’s lockdown from the 23March 2020. This resulted in the UK department of health instructing NHS Trusts todiscontinue most elective operating from the 15 April 2020 for a period of at least 3 months. The UK intercollegiate guidance issued re-prioritisation of surgicalprocedures and the careful planning of how to recover surgical services followingthe easing of COVID-19 preventive measures.4 Due to the unprecedented natureof COVID-19, it is unclear how the disease and preventive measures have impactedupon patient’s symptoms and care.As of the 17 June 2020, the United Kingdom had 299,600 confirmed cases and 42,054deaths, although it is thought the actual rates of cases and deaths may be higher. Prevalent opioid prescribing for non-cancer pain can lead to hypogonadism and substance abuse disorders; indeed 1–43% of patients with chronic painhave an opioid use disorder. Social isolation and loneliness are also thought to result from chronic pain,as well as be contributing factors to its emergence.810 Therefore, given the anxietysurrounding COVID-19, immunosuppressant effects of opioid administration13 and association between socialisolation and chronic pain,810 the COVID-19pandemic may present significant challenges to individuals with chronic painconditions.Chronic pain is characterised by severe pain that continues for longer than 12 weeksdespite medication or treatment. It has negative effects on quality of life and is acontributing factor to mental health problems. The prevalence of mood and anxietydisorders has been reported to range from 1% to 61% in chronic pain conditions. SCS significantly reduces pain in individuals with failed back surgerysyndrome (FBSS), complex regional pain syndrome (CRPS)17 and painful diabetic neuropathy. Health-related quality of life and pain-related disability improve with SCS. Also, decreases in medication consumption, such as opioids andanti-neuropathic medication, have been evidenced in research exploring the efficacyand safety of SCS.21 SCS can benefit patients who have failed other treatments.Spinal cord stimulation (SCS) is an National Institute for Health and Care Excellence(NICE)-recommended procedure for intractable chronic pain of neuropathic origin(TA159) and is provided in around 28 centres in the United Kingdom as a specialist service.Although not explicitly stated, National Health Service England (NHSE) guidelines forthe prioritisation of surgical procedures during the COVID-19 pandemic suggest thatSCS be considered priority category 4, although in certain clinical scenarios itcould be appropriately categorised as category 2 or 3. This ambiguity in prioritylevel may influence provider decision-making, and result in unacceptable and unfairdelays to chronic pain patients awaiting SCS; which could have a profound impact onthe physical and mental needs of a patient suffering with anxiety, severe pain and atendency to drug misuse. In addition, in a sample of 34 patients who underwent elective surgeriesduring the incubation period of COVID-19, all developed COVID-19 pneumonia shortlyafter surgery. The complexity of surgery also appears to be an important factor: the morecomplex the surgery, the greater the number of COVID-19 patients admitted to theintensive care unit (ICU). Furthermore, 30-day mortality has been estimated at around 24% for electiveand emergency surgery, with the risk of mortality from COVID-19 pneumonia in the perioperativeperiod being near 21% for procedures done both under general and local anaesthesia. However, it is important to note that these data are not specific to aparticular group of patients or type of surgery, rendering it unclear how muchvariability there is between clinical conditions and procedures for COVID-19 risk.In response, our study characterised the willingness of chronic neuropathic painpatients to undergo a neuromodulation procedure (SCS) and how chronic pain patientsview the balance of risk of COVID-19 infection versus the potential benefit ofSCS.Undergoing surgery during the COVID-19 pandemic is not without serious risks. Indeed,using mathematic modelling, of 91,410 elective surgery outpatients, at least 75.90(near 1%) would develop preventable patient infections in Washington State alone ifelective outpatient procedures continued as normal.Supplementary Section). This enabled us to obtain a national pictureof patients who are currently waiting for SCS therapy.This was a prospective, multi-centre telephone patient survey conducted during May2020 in seven UK centres. The study received local audit board registration. Allcentres used the same questionnaire  for chronic pain, at seven NHS hospitals. A small percentage of patientswere waiting to undergo surgical paddle lead implantation. No formal sample sizecalculation was conducted. Four hundred and three adults on an SCS waiting listwere contacted by telephone to take part in the survey of which 330responded.Supplementary Section) and categorising participants as eithervery high, high or low COVID-19 risk. Participants were also asked if they hadexperienced COVID-19 symptoms or been formally tested for the disease andoutcome of the test.Briefly, the survey elicited responses from participants on questions related totheir personal risk of mortality from COVID-19, the impact of lockdown on theirpain, mental health and intake of analgesia and their willingness to attendtheir local hospital for an SCS implant. COVID-19 risk was ascertained for eachparticipant. This was achieved using NHSE risk criteria . Data were analysed in SPSS (version 25) by a singleresearcher (B.B.) and counterchecked (G.B.). To analyse the data, counts andpercentages were generated. To explore the impact of COVID-19 risk  on survey responses, chi-square tests of independencewere undertaken. An alpha level of 0.05 was deemed statisticallysignificant. For the temporary trial, the trial wires are removed and patientsrelisted for a full implant. The permanent trial involves connecting the batteryto the wires at the end of the trial period.NICE TA159 recommends SCS for adults who have chronic neuropathic pain  for at least 6 monthsdespite more conservative management with medication and targeted injectiontreatment. SCS pathways vary between patients in order to address theirindividual needs. Briefly, the pathway involves assessment for suitabilityfollowed by information session, psychology assessment and multidisciplinaryteam (MDT) discussion. Opioid reduction may also be included, depending on thepatient and unit. Patients are then placed on a waiting list for surgery.Surgery involves a temporary trial or a permanent trial.Four hundred and three patients on an SCS waiting list were contacted and 330 took part in the survey (82% response rate). The demographiccharacteristics of the participants are displayed in The majority  experienced severe pain in the previous week see. 27%, with 50% (n = 162) of patientsreporting no change in pain. Deteriorations in pain were reported in 155patients (47%), with 72 (22%) stating pain was much worse compared to beforeCOVID-19. This was followed by 53 (16%) and 30 patients (9%) who reported painwas minimally worse and very much worse, respectively. There were missing datafor three patients. Change in pain was independent of COVID-19 risk. However, 139 patients (50%) reported deteriorations in mental healthsee . ThiscoChange in pain was significantly related to change in mental health demonstrated a highwillingness from patients to undergo SCS surgery and adhere to COVID-19 relatedprocesses. 302 patients (92%) were willing to attend for COVID-19 swabs  said they would be willing to undergo theprocedure with local anaesthetic with the option of being administered strongpainkillers see . When inWhen asked about the length of time patients would prefer to wait prior to havingtheir SCS procedure, most patients  stated a preference for havingthe procedure as soon as possible see . Forty-fTo our knowledge this is the first prospective, multi-centre telephone survey thatexamined how the COVID-19 pandemic has impacted chronic pain patients awaiting SCStherapy in the United Kingdom. Findings revealed that the COVID-19 pandemic wasassociated with deteriorations in pain (47% of patients), mental health (50%) andability to self-manage pain (38%). In addition, there was a sub-group of patientswho reported increases in pain medication consumption (37%) and reliance on supportnetwork (41%). However, with the prospect of surgery, most patients said they wouldbe willing to attend for COVID-19 testing (92%) and self-isolate prior to theprocedure (94%), with 76% of patients stating a preference to undergo surgery assoon as possible. These findings therefore suggest that despite the risks posed byCOVID-19, there is a strong clinical demand for SCS in patients with chronic pain,likely driven by severity of pain and challenges with mental health. This includes costs attributed to consultations, drugs, surgicalprocedures, non-surgical procedures and alternative therapies. Within 2 weeks of the outbreak of COVID-19 in China, it was reported thataround 54% of respondents to an online survey rated the psychological impact ofthe outbreak as moderate or severe. In addition, moderate to severe depressive, anxiety and stress symptomswere reported by 17%, 29% and 8% of respondents, respectively. Chronic pain patients are at a high risk for developing depression, social isolation can be a precursor to depression29 andcountries were shut down to stem the spread of COVID-19. Therefore, the effectsof the COVID-19 pandemic could have devastating consequences for the mentalhealth of individuals with chronic pain if current lack of access to SCSpersists. Indeed, findings revealed an association between change in pain andchange in mental health, suggesting the two are closely linked. With thecontinuation of the NHS Mental Health Implementation Plan, it is hoped thatthese patients will be able to receive the psychological support they need inorder to effectively self-manage their pain and prevent further impairment oftheir clinical condition and quality of life.Deteriorations in pain and mental health occurred in some patients as a result ofthe COVID-19 pandemic. The direct healthcare costs associated with neuropathicpain in the United Kingdom is estimated to be around €2951 per patient per year. In addition, the immunosuppressant effects of chronic opioid treatmentmay potentially increase COVID-19 risk.31 As prolonged analgesia usehas been associated with elevated mortality risk in osteoarthritis patients, the cardiac and COVID-19 risks of SCS patients need to be carefullyconsidered and quantified. This is compounded by limited clarity concerning theassociation between high doses of opioids, immune suppression and COVID-19.Therefore, the prioritisation of patients for SCS implant should take intoaccount changes in pain medication that have occurred since the beginning of theCOVID-19 pandemic.Although some patients were relatively effective at self-managing their pain(i.e. pain medication consumption stayed the same and reliance on supportnetworks did not increase), this was not the case in other patients. Indeed,around 37% of patients reported increases in pain medication consumption. Thesefigures are concerning given that opioids may theoretically mask or delay thedetection of symptoms of COVID-19, such as myalgia, cough and shortness of breath. One study, for example, assessing broader cost of illness in chronic painpatients estimated mean annual societal costs to be €10,191 per year. As many workers have been furloughed or made redundant during thepandemic, the working lives of these patients may have been disrupted, in turnhaving further negative effects on the economic costs associated with theircare. Productivity loss is also an element of the societal costs documentedabove; accounting for approximately 40% of costs. Worsening of symptoms may further impact a patient’s ability to work,compounding these productivity losses, and may also have a significant impact onthe patient in a time of employment uncertainty. SCS is an effective treatmentthat may support an individual’s ability to work, and this may be an additionalconsideration concerning timely access. Further research investigating methodsthat influence these costs (e.g. timely intervention) may be warranted.Around 41% of patients reported increased reliance on support networks during thelockdown due to increased pain severity. Enhanced carer burden/informal care hasbeen associated with increases in societal costs. Indeed, annual professionalcaregiver costs are reported to be in the region of €1242 in the United Kingdom,but this is thought to constitute a small proportion of total care as most careis provided informally by friends and/or family. Despite these risks, most patients, including very high COVID-19 riskpatients, stated a strong willingness to attend for SCS therapy, showing apreference for the surgery to happen as soon as possible. This thereforedemonstrates a high clinical need for SCS in chronic pain waiting list patients,perhaps due to the humanistic impacts of the condition: enjoyment of life, mood,activity, work, relationships, sleep and employment are significantly impacted. In addition, pain profoundly disrupts everyday functioning (Brief PainInventory (BPI) score: 4.80) and has been associated with low quality of life(EuroQol-5D (EQ-5D) score: 0.57).36 Quality-adjusted lifeyears (QALY) loss has been reported to be 64% in patients with chronicdiscogenic low back pain with around 98% (78/80) of patients showing somephysical limitations. To more fully understand how COVID-19 impacts the presentation of chronicpain, validated questionnaires that quantify pain, including the contribution ofneuropathic elements, pain-related disability, quality of life, QALY and theimpact of pain on daily functioning, should be employed. These data could thenbe used to stratify patients and prioritise those who are in urgent need oftherapy and can safely undergo the procedure. Although there is little datapertaining to the willingness of patients to attend for non-mortality relatedinterventions, with increasing research into the impact of COVID-19 in otherspecialities, it is hoped that comparisons will be possible in time.The COVID-19 pandemic presents numerous risks to patients which may provokedepression, anxiety and stress. Furthermore, the quality of communication between healthcareprofessionals and patients, combined with reports in the media, will profoundlymodulate how patients perceive their current and prospective treatment. Thistherefore calls for future research to systematically monitor the effects ofdelayed treatment over the long term. This could include evaluating theeffectiveness of the e-tool: a new clinical resource to support referrers and implanters in optimisingpatient flow into secondary care through supporting appropriate referrals andmaximising outcomes of patients who ultimately go on to receive SCS. It is hopedthis will promote the efficient and optimal use of resources. Combined with theneed to reduce treatment delays, the e-tool may also reduce unnecessary trialprocedures and more effectively address the needs of patients requiring SCS.With the gradual easing of rules surrounding COVID-19, the reuptake of electivesurgeries needs to be carefully managed and monitored. Given delays in treatmenthave occurred for some patients during the COVID-19 pandemic, these impacts needto be comprehensively assessed. Indeed, in normal times, delays to treatment addavoidable costs to the patient journey. For instance, for every 1-year increasein the time between a chronic pain diagnosis to SCS implantation, the likelihoodof consuming more opioids, having more hospitalisations, healthcare appointmentsand medical expenditures increases. Of course, with research investigating the ongoing situation, it is hopedthat greater clarity can be achieved in order to maximise patient safety whilefulfilling their healthcare needs.To our knowledge, this is the first survey exploring how the COVID-19 pandemichas impacted chronic pain patients on a neuromodulation waiting list in theUnited Kingdom. Importantly, these findings are specific to SCS, providing afocussed account of how this patient cohort is coping with their symptoms duringthe pandemic. However, as these findings are based on data collected during thefirst 2 months of the UK lockdown in a specific group of patients, it is crucialto repeat surveys of this kind in this and other patient groups. Of course,these data need to be substantiated internationally, which will hopefully aidwith overcoming challenges associated with providing quality healthcare duringpublic health crises. From a methodological perspective, the telephone nature ofthe survey presented advantages over more traditional paper-based approaches.This avoided potential reluctance on behalf of the patient to handle paper andreduced response time, potentially contributing to the high response rate (82%).Despite positive views towards attending for surgery, patients were not advisedabout the precise and as yet unquantified serious risks of elective surgeryprior to responding to the survey. Therefore, the high rate of participantsstating a willingness to attend for their procedure may not be an accuratereflection once patients and clinicians are more reliably informed with morepublished data. This is compounded by the fact that since the COVID-19 pandemicis a rapidly changing situation, it is difficult for healthcare professionals tofind clarity about the risks of elective surgery and indeed care for patientswith pain during these times.Findings from this prospective telephone survey revealed that most chronic painpatients on an SCS waiting list experienced deteriorations in pain and mental healthduring the COVID-19 pandemic. Although some patients reported no adverse effects onability to self-manage pain, increases in pain medication and reliance on supportnetworks were acknowledged. The prospect of SCS surgery was well-received, with mostagreeing to undergo testing, self-isolation, attending on the day of the procedureand preferring the surgery to happen as soon as possible. These findings suggestthat even during unprecedented times, the clinical need for SCS in chronic painpatients is strong.


Carpal tunnel syndrome is the most common nerve compression disorder of the upper extremity, and it is traditionally considered a peripheral neuropathy associated with a localized compression of the median nerve just at the level of the carpal tunnel. Surgery and physiotherapy are treatment approaches commonly used for this condition; however, conflicting clinical outcomes suggest that carpal tunnel syndrome may be more complex. There is evidence supporting the role of peripheral nociception from the median nerve in carpal tunnel syndrome; however, emerging evidence also suggests a potential role of central sensitization. The presence of spreading pain symptoms , widespread sensory changes, or bilateral motor control impairments in people presenting with strictly unilateral sensory symptoms supports the presence of spinal cord changes. Interestingly, bilateral sensory and motor changes are not directly associated with electrodiagnostic findings. Other studies have also reported that patients presenting with carpal tunnel syndrome exhibit neuroplastic brainstem change supporting central sensitization. Current data would support the presence of a central sensitization process, mediated by the peripheral drive originating in the compression of the median nerve, in people with carpal tunnel syndrome. The presence of altered nociceptive gain processing should be considered in the treatment of carpal tunnel syndrome by integrating therapeutic approaches aiming to modulate long-lasting nociceptive barrage into the central nervous system  and strategies aiming to activate endogenous pain networks . Since people affected by CTS are usually active workers, this condition is associated with substantial healthcare costs and economic burden3. Therefore, a better understanding of the potential underlying mechanisms of CTS could improve therapeutic strategies. This paper discusses current theories combining the presence of peripheral nociceptive barrage with the presence of altered nociceptive central processing and its repercussions for the potential management of CTS. The current paper is an updated version of a previous review on this topic4.Carpal tunnel syndrome (CTS) is the most prevalent nerve compression disorder of the upper extremity, and it is generally associated with a localized compression of the median nerve in the carpal tunnel area. Although epidemiological data vary depending on the diagnostic criteria used, CTS has an incidence rate of 1.8/1,000This review will try to answer the following questions: 1. is CTS just a localized peripheral entrapment of the median nerve? 2. What are the underlying mechanisms behind the clinical manifestations of CTS? 3. Does the presence of altered nociceptive gain potential have repercussions on treatment approaches in CTS?5.The most common symptoms usually experienced by patients with CTS include pain and/or paresthesia in areas innervated by the median nerve, i.e. the thumb, index, and/or middle fingers. Symptoms can be worse during activities involving the hand/wrist but also at night. It seems that paresthesia, but not pain, is the symptom most commonly associated with neurophysiological damage of the median nerveet al., who observed that 35% of patients with CTS exhibit a glove distribution of their symptoms, whereas 5% exhibit an ulnar distribution6. The same authors also reported that 45% of CTS sufferers also report pain in proximal areas of the upper extremity including the elbow or the shoulder7. A more recent study, using new electronic software for analyzing pain extent, found that 88% of women with CTS showed extra-median pain symptoms8. The presence of spreading symptoms is a clinical manifestation of neuropathic but also nociceptive pain involving sensitization mechanisms and plasticity9. This hypothesis is confirmed by the fact that extra-median symptoms are not associated with electrical nerve conduction data, suggesting an association between neuropathic and nociceptive pain with expansion of receptive fields of central neurons in CTS10.It is commonly seen in clinical practice that patients with CTS exhibit symptoms not only in those areas innervated by the median nerve but also in extra-median nerve areas. This was confirmed by Zanette12. ‘Peripheral sensitization’ refers to increased responsiveness and reduced threshold of peripheral nociceptors; it is usually associated with the release of endogenous algogenic substances and neurogenic inflammation. ‘Central sensitization’ is defined by the International Association for the Study of Pain (IASP) as an increased responsiveness of the nociceptive neurons in the central nervous system to their normal or subthreshold afferent input, which may include increased responsiveness due to dysfunction of endogenous pain control systems13. The relationship between peripheral and central sensitization is well established. It is accepted that the presence of long-lasting and prolonged nociceptive peripheral inputs induces plastic changes in the central nervous system; therefore, central sensitization seems to be a dynamic process that is dependent on peripheral nociception12. In some patients, once central sensitization has been established, minimal peripheral nociception can be required to maintain this process and non-nociceptive inputs might also contribute to the subsequent pain and mechanical allodynia observed in this situation. Nevertheless, central sensitization is mainly driven by peripheral impulses. In such a scenario, in people with CTS, the entrapment of the median nerve at the carpal tunnel represents the peripheral input towards the central nervous system. Gracelyet al. proposed this model for neuropathic pain in 1992 where peripheral nociception from an entrapped nerve could lead to neuroplastic changes in the central nervous system14. In CTS, the neurogenic inflammation of the median nerve induced by its entrapment can act as a peripheral driver for the gradual sensitization of nociceptive pathways. In fact, Truiniet al. found that affectation of both nociceptive and non-nociceptive fibers contributed to the different symptoms experienced in CTS15.‘Sensitization’ is a term describing the changes in nociceptive neurons. It is mainly grouped into peripheral/central sensitization, and it is present in several musculoskeletal and neuropathic chronic pain conditions16 and will not be further discussed in this text. In the last decade, different studies have investigated the presence of central sensitization by assessing widespread sensory disorders throughout quantitative sensory testing in CTS. Fernández-de-las-Peñaset al. found that women with strictly unilateral CTS symptoms exhibit widespread pressure pain sensitivity over the radial, ulnar, and median nerves, the cervical spine, and the tibialis anterior muscle, suggesting widespread hypersensitivity to pressure pain17. Widespread pressure hypersensitivity is a manifestation of the sensitization of central pathways; however, pressure pain hypersensitivity has also been found to be heterogeneously distributed in the symptomatic hand, supporting the relevant role of the peripheral input18. Similar results were also found by Zanetteet al., who observed that CTS patients with extra-median symptoms exhibited generalized pressure hyperalgesia and enhanced wind-up19. Interestingly, widespread pressure pain hyperalgesia was not associated with the electrodiagnostic findings, since women with minimal, moderate, or severe CTS exhibit similar widespread sensory changes20. These results support the notion that widespread hyperalgesia to pressure pain can be a common manifestation of CTS from the beginning of symptom onset. In line with this hypothesis, Tampin, Vollert, and Schmid found that individuals with a peripheral neuropathy such as CTS exhibit similar sensory changes to those with a proximal  radiculopathy, although pain profiles were different21. Nevertheless, Schmidet al. did not observe widespread pressure hyperalgesia in patients with CTS without concomitant neck pain symptoms, suggesting that groups of patients with CTS could exist and that the observed widespread sensory changes can be more related to the presence of extra-median/proximal symptoms22. The hypothesis of different subgroups of patients with CTS has been supported by a study identifying a subgroup of women with CTS with higher bilateral widespread pressure hyperalgesia based on the presence of a cluster of symptoms23. Therefore, it is possible that CTS can be peripherally mediated in some patients but more centrally mediated in others.The peripheral component of entrapment neuropathies such as CTS is supported by current literatureThe presence of central sensitization in CTS is also supported by imaging studies. et al. found that patients with CTS with symptoms of glove distribution exhibited an enlargement in cortical representation and neuroplastic changes in the somatosensory cortex compared to those individuals with just median nerve distribution symptoms24. Different studies have also shown larger contralateral sensorimotor cortical representation25 and smaller cortical source separation26 of the second/third digits in patients with CTS as compared to controls. All of these studies hypothesized that long-lasting paresthesia/pain symptoms  can promote blurring of median nerve-innervated digit representations through neural mechanisms 26. There is also current evidence showing the presence of reduced endogenous inhibition and increased pain facilitation in patients with CTS27. In conclusion, long-lasting peripheral nociceptive stimuli originating in the median nerve could lead to neuroplastic changes in the central nervous system at both spinal cord and brainstem levels.Tecchio28. The presence of bilateral deficits in fine motor control and pinch grip force in women with strictly unilateral CTS supports this hypothesis29. Additionally, these bilateral deficits in fine motor control and pinch grip force were not associated with either median nerve damage or the presence of unilateral or bilateral symptoms30. Data suggest that motor output disorders are present from the onset of symptoms and could be related to neuroplastic changes in the cortex. Nevertheless, it is probable that peripheral and central mechanisms can be involved at the same time in the motor control disturbances observed in CTS.It is interesting to consider that sensitization mechanisms and sensory loss also have output manifestations. Motor control disturbances may be a perpetuating factor for pain since pain-related fear or avoidance behaviors can also promote negative attitudes. In addition, altered motor control patterns could reflect the reorganization of motor control strategies in the central nervous system, as sensory neuroplastic changes in the somatosensory cortex result in decreased fine motor control31. In fact, both open and endoscopic surgical interventions provide similar clinical results32. However, although surgery provides positive long-term results, it may not always be entirely successful33, and the recurrence rate is estimated to be around 30% (from 5 to 57%)34. There is great debate related to which patients with CTS should be treated with conservative or surgical treatment in the first instance35. In fact, no consensus exists on which therapeutic option is the best for CTS. A recent meta-analysis has reported that the differences between surgery and conservative treatment are small36. Interestingly, Jarviket al. observed that 61% of patients with CTS attempted to avoid surgery37. Conservative treatment for CTS could be preferred as the first-line option for patients with minimal or moderate CTS, whereas surgery could be the first-line approach for patients with more severe symptoms or when conservative treatment has failed.Although CTS can be treated with conservative and surgical procedures, surgery continues to be the most common treatment approach proposed for these patients38, i.e. physiotherapy.It is important to consider that there is no established algorithm for determining which patients with CTS will benefit from conservative treatment39, ultrasound40, or splinting41. Other conservative techniques, e.g. nerve/tendon (neuro-mobilization) gliding exercises, have shown promising, but also limited, outcomes42. Discrepancies in the effects of multiple and different management therapeutic strategies can be attributed to the fact that CTS is a heterogeneous syndrome. In such a scenario, the presence of sensitization mechanisms discussed in this text could provide a physiological explanation for those individuals with CTS who experience persistent symptoms despite apparently successful surgery.In fact, different meta-analyses reported inconclusive evidence for the use of different conservative interventions, such as low-level laser44. In patients with centrally mediated symptoms, clinicians should incorporate therapeutic approaches directed at normalizing peripheral and central nervous system interactions  and not just localized interventions over the carpal tunnel. It is in this group of patients where medications targeting the central nervous system could be effective45.A mechanism-based classification can help clinicians to understand that different signs and symptoms may reflect different underlying nociceptive gain mechanisms. The presence of sensitization mechanisms in people with CTS has potential implications for clinical practice, since it implies that, in some patients, more global, not just localized, interventions should be applied. According to current data, clinicians should identify if symptoms in a patient with CTS are mainly peripherally or centrally mediated. In patients with peripherally mediated symptoms, localized interventions targeting local tissue  should be provided. There is evidence supporting a peripheral effect of nerve/tendon gliding exercises in patients with CTS, since these exercises affect the biological integrity of the median nerve by increasing fluid dispersion and reducing intraneural edema46. This promising clinical trial showed that the application of manual therapies following altered nociceptive gain reasoning exhibited better short-term (1- and 3-month) and similar long-term (6- and 12-month) effects on pain and function than surgery in women with CTS46. In fact, the cost-effectiveness analysis of this trial also revealed better economic aspects in favor of manual physical therapy47.This clinical reasoning has been applied in a randomized clinical trial comparing the effects of manual therapy including desensitization maneuvers of the central nervous system with surgery in women with CTS48. A recent study has reported that localized, but not widespread, pressure sensitivity was predictive of long-term clinical outcomes in a sample of women with CTS after the application of manual therapies including desensitization maneuvers of the central nervous system49. These preliminary results support the clinical reasoning that not all patients with CTS respond to the same therapeutic approach and subgroups of patients could exist.Nevertheless, the challenge facing clinicians is how to select the most appropriate intervention for each patient, who is likely to be slightly different in their presentation. To determine the most appropriate therapeutic strategy, considerations must be given to interpreting the clinical manifestations of these sensitization processes  and to potential prognostic factors related to clinical outcomes. Nevertheless, although central sensitization has been related to poorer outcome in response to surgical or conservative treatment in musculoskeletal pain, this hypothesis is supported by small and exploratory studies, and no conclusion can be made for this assumptionThis updated review of underlying mechanisms of CTS found that there is evidence supporting the presence of central sensitization mechanisms, potentially mediated by the peripheral nociceptive inputs from the median nerve, in patients presenting with CTS. The presence of central sensitization influences treatment prognosis and the response of patients with CTS to a particular therapeutic strategy. The current paper has proposed the existence of two main subgroups of patients: those with peripherally mediated CTS and those with centrally mediated CTS. Clinicians should apply therapeutic strategies based on current knowledge on pain neuroscience and according to the clinical presentation and predominant identified mechanisms in these patients.


Effectiveness of sufentanil sublingual tablet system (SSTS) compared to oral oxycodone in the management of postoperative pain after total knee arthroplasty (TKA) within an enhanced recovery after surgery (ERAS) protocol.This pragmatic, parallel, open label, randomized controlled, trial enrolled 72 adult patients scheduled for TKA under spinal anesthesia following ERAS pathway. In addition to multimodal analgesia, patients received SSTS 15 mcg (SSTS group) or oral oxycodone extended release 10 mg twice daily and oral oxycodone immediate-release 5 mg up to four times daily on demand (Oxy group) to control pain during 48 h postoperatively. The primary endpoint was pain measured using a numeric rating scale at 24 h postoperatively. Time to first mobilization, side effects and patient satisfaction were also recorded.p = 0.272) whereas median pain score on movement was 4 [3–6] vs 3 [2–5] respectively (p = 0.059). No difference in time to first mobilization was found between the two groups. The method of pain control was judged good/excellent for 83.9% of patients in the SSTS group compared with 52.9% in the Oxy group (p = 0.007). The incidence of nausea was 33% in SSTS group and 9% in Oxy group (p = 0.181).Median pain score at 24 h at rest was 3 [2–4] for Oxy group vs 2 [1.75–3] for SSTS group (In complement to ERAS multimodal analgesia, sublingual sufentanil 15 mcg tablet system did not show clinically significant pain improvement compared to oral oxycodone after total knee arthroplasty.NCT04448457; retrospectively registered on June 24, 2020. https://clinicaltrials.gov/ct2/show/NCT04448457?cond=sublingual+sufentanil&cntry=BE&draw=2&rank=3Clinical Trials:  Total knee arthroplasty (TKA) is a common procedure expected to grow in the near future . To copeSufentanil is a potent synthetic μ receptor-specific agonist which is mainly used for intraoperative surgical analgesia. When given via sublingual route sufentanil shows a rapid onset due to high lipophilicity, a good bioavailability (60%) and a prolonged duration of action in comparison with IV sufentanil , 19. ThoTherefore, we conducted this trial to compare the efficacy of SSTS to oral oxycodone in the management of postoperative pain after TKA within an ERAS protocol. We hypothesized that SSTS could show a better profile on pain control, mobilization and patient satisfaction.The primary endpoint of this study was to compare the effect of SSTS with oral oxycodone on pain intensity at 24 h postoperatively.ClinicalTrials.gov (NCT04448457). Inclusion criteria were adult patients (age ≥ 18 years) scheduled for unilateral total knee arthroplasty under spinal anesthesia, American Society of Anesthesiologists (ASA) class 1–3. Exclusion criteria were contraindications to our ERAS protocol, allergy to study medications, history of addiction or preoperative chronic use of opioids, unicompartmental or revision knee replacement.The study was a pragmatic, single-center, prospective, open label, randomized controlled trial conducted at CHU Tivoli Hospital, La Louvière, Belgium, to show the superiority of SSTS over oral oxycodone on pain control after total knee arthroplasty. The study design was approved by the Ethical Committee of Erasmus University Hospital, Brussels (ref P2017/348 on 21/06/2017). All patients signed an informed consent and the study was performed in accordance with the declaration of Helsinki. The study was registered retrospectively with All patients received oral midazolam, dosed at the discretion of the anesthesiologist, as anxiolytic premedication. Following the institutional ERAS protocol, 2 g cefazolin, 125 mg methylprednisolone and 1 g of tranexamic acid were administered intravenously 30 min prior to incision. Spinal anesthesia was performed with 8–12 mg of hyperbaric bupivacaine 0.5% without adjuvant. As part of the multimodal pain management protocol, all patients received by the surgeon local infiltration analgesia with 200 mL of ropivacaine 0,2% . At the end of the surgery 3 g of tranexamic acid diluted in 70 mL of NaCl 0.9% were injected intraarticularly. All surgical procedures were performed by the same three surgeons without tourniquet and no drain was left in place.At the arrival in post-anesthesia care unit (PACU), if necessary, pain was initially treated with IV piritramide until discharge criteria to the ward were met. For the postoperative multimodal pain management, application of ice pack on the wound area, acetaminophen 1 g PO four times daily and celecoxib 200 mg PO one time daily were given systematically to all patients. Postoperative nausea and vomiting (PONV) prophylaxis was administered according to institutional guidelines.Patients followed our institutional rehabilitation protocol which consists of lifting the patient by the physiotherapist as soon as he returns from the recovery room, the patient is also seated whenever it’s possible on day 0 (day of surgery). On day 1, the patient starts passive motion machine , exercises in the physiotherapy room, occupational therapy program, and so on, on day 2.Patients were randomly assigned to study groups  in fixed blocks of 4 using computer-generated random numbers kept in sealed envelopes. Envelope was opened at the arrival of the patient in the operating theater and subjects were allocated to the sublingual sufentanil tablet system (SSTS) group or the oral oxycodone (Oxy) group.Patients enrolled in the SSTS group were instructed for the use of the device in PACU and the first dose was administered there allowing sublingual administration of sufentanil 15 mcg tablet with a fixed 20-min lockout interval. In the Oxy group, patients received oral oxycodone extended-release (ER) 10 mg twice daily and oral oxycodone immediate-release (IR) 5 mg up to four times daily on demand when numeric rating scale (NRS) > 3. In case of insufficient pain management, patients could receive rescue intramuscular morphine injection and patients would be automatically excluded from the study.Primary endpoint was pain score at 24 h postoperatively. Pain was assessed using a verbal 11-point numeric rating scale (NRS-11) ranging from 0 (“No pain”) to 10 (“Worst imaginable pain”). The verbal NRS-11 is a well validated, reliable and sensitive tool to evaluate acute postoperative pain . PatientSample size calculation was estimated on the basis of an absolute reduction of NRS score in SSTS group compared to Oxy group. Analysis of pain scores obtained before the start of the study on 7 patients treated by oxycodone indicated a mean pain score of 5.587 with a standard deviation of 1.46 at 24 h after surgery. In order to show a difference of 2 points of NRS score with a power of 0.9 and a bilateral alpha risk of 0.05 we calculate the need of 28 patients per group, considering a minimal clinically important difference of 1. Taking into account an estimated drop-off of 20%, we conclude that a total of 70 patients were needed. We used the ‘Trial Size’ package of the R software to perform the sample size calculation.25–Q75]) are reported. For count data, the Pearson Chi-Squared test was performed to compare proportions. For time to event data, Kaplan–Meier product-limit estimators of cumulative rates of patients reaching the event (success of first mobilization) at follow-up time points were calculated. A log-rank test was used to compare the two treatment groups. We used the software R, version 3.4.3  to perform the statistical analyses. Prism version 8.4.2  was used to construct the figures.Continuous data were compared by means of T-test when homogeneity of variances, tested with the Bartlett’s test, and normality of the residuals, tested with the Shapiro-Wilks test, were reached and means and standard deviations (SD) are reported. When homogeneity of the variance or normality of the residuals were not proved, Wilcoxon signed rank test was performed on rank data and medians and interquartile ranges ( Oxy group vs 2 [1.75–3] for SSTS group (p = 0.272) whereas median dynamic pain score was 4 [3-6] vs 3 [2-5] without hyperlink respectively (p = 0.059)  in SSTS group at rest, and 23 (65.7%) vs 15 (44.1%) (p = 0.071) respectively on movement. No statistical differences were found neither in static nor in dynamic pain over the 48 h postoperative period . Three (8%) patients suffered vomiting in the Oxy group and 4 (11%) in the SSTS group (p = 0.690). One patient complained of pruritus in the Oxy group. As shown in Fig. p = 0.007) , one could argue on the clinical relevance of this result. The lack of multimodal analgesia as well as the absence of an effective control group could explain the pronounced effect of SSTS in these studies. This hypothesis is supported by the lack of difference on postoperative pain scores when SSTS was compared with continuous morphine after cardiac surgery  summed pain intensity difference (SPID) from baseline over 48 h (SSTS 105.6 [10.14] vs placebo 55.58 13.11]) after open abdominal surgeries . Similar) after o surgery . After m surgery . Because surgery , 21 but  surgery . This op surgery . SimilarIn our ERAS pathway, more than 80% patients in both groups were mobilized on day 0. With this high success of first mobilization the role of SSTS in functional outcome as early mobilization seems to be limited.Incidence of adverse events was limited, but 33% of patients for SSTS group versus 9% of patients for Oxy group reported nausea during the 48 h which is in accordance with the literature . Even ifConcerning the use of the system, we found some issues with the operation of the device, we noticed always the same problem: the thumb tag had to be replaced for three patients, especially at the beginning of the study.Regarding the limited efficacy of the system and the high prevalence of nausea, the economic burden seems not to be justified even if patient satisfaction is improved. Indeed, in our hospital, the cost of one tablet of Oxynorm IR is €0.085, Oxynorm ER is €0.125 and the cost of the 40 tablets cartridge is €105. Regarding the mean consumption in each group, the total cost over 48 h is €1.195 for Oxy group and €105 for SSTS group. The price of the device (around €1400) as well the cost of the thumb patch should also be taken into account. Our study had several limitations. The use of mean NRS at 24 h as the primary endpoint may be less sensitive than SPID to detect a difference between treatment. The open label design could have influenced the PGA as explained above.In complement to ERAS multimodal analgesia, sublingual sufentanil 15 mcg tablet system did not show significant pain improvement compared to oral oxycodone after total knee arthroplasty.


Long-term symptoms after whiplash injury often comprise neck pain, headache, anxiety, depression, functional impairment and low quality of life. In an observational cohort study, we examined physical and mental health effects in patients with subacute to chronic whiplash-associated disorders (WAD) after participation in a multimodal rehabilitation (MMR) program. MMR is a team-based multi-professional method based on a bio-psycho-social model with a cognitive focus to reach an individualized and common goal for the team and patient together. Standardized self-report questionnaires were filled in three times: before MMR, after MMR, and one year after MMR. A total of 322 participants completed the program, 161 of whom responded in full and were further analyzed. At one-year follow-up after MMR, a significant improvement was seen in the evaluation of the primary outcomes  and secondary outcomes . Women improved on all outcomes while men did not improve on the psychological measures . This study indicates that a MMR program could be beneficial for patients with subacute to chronic WAD, at least for women, since the outcomes at one-year follow-up were positive. Road accidents are a common cause of traumatic neck injury/whiplash injury. The incidence of whiplash injuries in Sweden is between 1.0 and 3.2/1000 persons per year . Early sAccording to a report from the Swedish Whiplash Commission 2006), patients with long-term WAD should undergo rehabilitation which follows the same recommendations as other patients with long-term pain 006, pati with a cThere is a lack of knowledge on what the long-term effects are for patients with WAD after they have undergone MMR programs where multiple disciplines are included and where a bio-psycho-social model is in focus. In addition, it is of interest to investigate potential gender differences in rehabilitation, not least because there is an overrepresentation of women with conditions of chronic WAD and there is also a knowledge gap regarding gender-related differences on the effects of MMR. Thus, the aim of this study was to evaluate the long-term effects of MMR for patients with WAD at one-year follow-up, regarding Health Related Quality of Life, anxiety and depression, pain intensity and interference with activity. Another aim was to investigate whether there were any differences between men and women regarding the results after MMR.This was an observational cohort study on patients with WAD with a one-year follow-up. Karolinska Institutet, Department of Clinical Sciences, Division of Rehabilitation Medicine, Danderyd Hospital, Stockholm, Department of Rehabilitation Medicine, Danderyd University Hospital.Data were based on patients participating in an MMR program between 2009 and 2015. All patients filled in questionnaires from the Swedish Quality Registry for Pain Rehabilitation (SQRP) . The stuInclusion criteria for the MMR program and this study were (i) WAD grade I  or WAD grade II  according to the Quebec Task Force Classification of Grades of Whiplash Association Disorder ; (ii) agIn the majority of cases, the patients were referred by their primary care physician to the Department of Rehabilitation Medicine, Danderyd University Hospital. After referral, a nurse made a primary assessment of the patient’s life situation and started the process of setting goals and informing the patient about the program. The patients were assessed by multi-professional teams  before their participation in MMR. The physician’s, assessment included the following: a pain history and clinical examination to exclude serious underlying conditions, referred neck pain; need of further investigations, e.g., imaging, blood tests, other specialist referrals; and/or optimization of the pharmacological treatment. If the patient decided to take part in the program and if the inclusion criteria were fulfilled, the patient and the other team members assembled to do a more in-depth assessment of the patient’s life situation. The disciplines included in the program were the same as in the assessment. All the disciplines were given more or less the same amount of time. All had comprehensive knowledge and experience of WAD-related rehabilitation. The duration of the program was five weeks with a total of 17 sessions, each lasting for 1.5 h with 1–3 sessions a day, 2–3 days a week. The patients were in groups of eight, they participated in all sessions and peer learning was facilitated by two patients being admitted and two patients discharged every week. One of the tasks of the nurse and the physiotherapist was to inform the patients about symptoms related to WAD, pain physiology, mechanisms related to the injury and healing, pain medication, pain management, the relationship between pain, bodily signs, behavior and emotions, and, together with the social worker, to give information on social rights and insurance. A group discussion based on a social and psychological perspective was conducted with the social worker and the psychologist. If needed, individual meetings were arranged with the psychologist. In addition, the physiotherapist handled sessions of 1.5 h per week on body awareness, relaxation and physical activity, and patients could also get a prescription for a transcutaneous electrical nerve stimulation device (TENS). The occupational therapist held sessions of 1.5 h per week on ergonomics regarding sleep, work and daily activities, how to balance activity and rest, and EMG bio-feedback. There were also 30-minute scheduled walks every week with a focus on mindfulness. The aim of the program was to help the patients reach an acceptance of their situation and to encourage a successive return to activities and participation, all through early rehabilitation. At the end of the MMR program, a plan was set up by the patient and the physician together for how the patient would be able to return to work. The physiotherapist gave individualized recommendations on physical activities and a nurse ended the program with a final visit with a discussion on further self-management strategies for optimal individual rehabilitation.Patients filled in questionnaires from the SQRP  before MSF36 ,25 is usHAD  is a queNRS  is a meaChanges are: 10–20% minimal important, ≥30% moderately, ≥50% substantial.The MPI  is a selAn assessment of data was performed before the MMR commenced, immediately after and one year after the completed MMR. Statistical Packages for the Social Sciences, version 22.0, , were used for data preparation and statistical analysis. Descriptive statistics were used to describe the population of the study. Data are reported as means with SD and medians. A chi-square test and Fischer´s exact test were used for frequency data. The Mann–Whitney U-test was used to compare the different groups´ demographic data and outcome scores at baseline. The Friedman test was used for analyses over time and the Wilcoxon signed ranks test was used for post-hoc analysis. The significance level was set at 0.05.This study was conducted in accordance with the ethical principles of the World Medical Association Declaration of Helsinki. In accordance with the routines of the SQRP, all subjects received written information that the questionnaires might be used for research purposes and that participation was entirely voluntary. Informed consent was received from all participants. The data were collected as part of the ongoing quality management of clinical care activities in the participating departments, and the data were stored with the consent of the National Swedish Data Inspection Agency (permission no. 1580-97). All possible identifications were deleted before statistical analysis.A total number of 322 participants were enrolled in the MMR program. Patients who failed to complete one or more of the three questionnaires were excluded. An amount of 18 patients did not answer after MMR and a further 143 patients did not answer at follow-up. The total number of non-respondents was 161 patients as illustrated in n = 161), with excluded patients, or non-respondents (n = 161). There was a significant difference in gender with a higher proportion of men among non-respondents (58.4%) than in the group of respondents (41.6%) (p = 0.022), At baseline, the non-respondents had significantly higher depression scores (p = 0.016), and anxiety scores on the HAD (p = 0.044)) and a significantly lower rate in physical health on the SF-36 (p = 0.011) than the group of full respondents. No significant differences existed between the groups regarding age, country of birth, job status, pain duration, conviction of recovery and expectations on when and how return-to-work would be. We compared patients who had completed all three questionnaires, denoted as respondents (p = 0.017) with a higher proportion of men born outside of Europe in comparison with women. Regarding educational level, 21.2% of the men and 38.5% of the women had completed university education. The mean number of anatomical regions affected by pain was 10.57 (SD 5.28) out of 36 pre-defined regions with no significant difference between women and men (p = 0.359). Background data and characteristics of pain are presented in p < 0.001). Mental health improved significantly for women (p < 0.001) at one-year follow up, but not for men (p = 0.157).In total, a significant improvement was seen for the primary outcomes of SF-36 see . For thep = 0.002) and depression (p = 0.044) was seen which is also reflected in a significant proportional change at follow-up compared with baseline for patients scoring moderate/severe anxiety from 78% to 38% (p < 0.001) and depression from 35.4% to 29.8% (p = 0.026) on the HAD. Anxiety in men was significantly improved after MMR (p = 0.008) but not at one-year follow-up (p = 0.118), whereas women improved significantly only after one year (p = 0.002). Regarding pain intensity on the NRS, there was a significant reduction after MMR and at one-year follow-up (p < 0.001) in all patients. The results for MPI-interference with activity showed a significant improvement for all patients both from baseline to after MMR (p < 0.001) and from baseline to one-year follow-up (p < 0.001). For the group of all patients, the secondary outcomes showed a significant improvement from baseline to after MMR and from baseline to one-year follow-up see . A totalThis study shows positive effects in patients with subacute to chronic WAD with regard to physical and mental health, anxiety and depression, pain intensity and activity after participation in a five-week outpatient MMR program and at one-year follow-up. The findings indicate a potential effectiveness of MMR in a long-term perspective for patients with WAD, with a greater improvement of mental health and depression in women. While women showed significant positive results for these psychological factors, for men, some of these aspects worsened. Pain intensity and activity were significantly improved in all the received questionnaires.p <0.001, ES 0.71). In that study, no observation was carried out on gender groups specifically. Although the program studied was similar to ours regarding content and number of professions, the patients were enrolled on the program at a later stage after trauma (“time since trauma”: 10 months) than the patients in our study (“mean duration of pain”: three months). Also, some other previously evaluated MMR programs for WAD patients included only one discipline, such as a physiotherapist [A detailed analysis of the results in our study reveals that a significant improvement was seen in physical health, both after MMR and at one-year follow-up. This is in line with results from some earlier studies. However, our results reveal persisting positive results for a longer time perspective than that in other studies. A comparable rehabilitation program to ours was examined in a study by Angst et al.  on WAD pherapist ,21,22 orherapist  and someherapist . In a stherapist , a physiherapist ,15,16,17Subacute to chronic WAD is a heterogenous condition that includes a complex interaction of psychological and physical factors. The population of all patients in the present study showed a significant improvement at follow-up for psychological factors of mental health, anxiety and depression. Conflicting results to this were seen in a previous study of patients with WAD participating in a rehabilitation program where no significant improvement in these variables were seen at follow-up after six months . HoweverDifferences between men and women were found regarding psychological measures. Women showed significant improvement regarding mental health and depression at one-year follow-up, while the corresponding improvement was not shown in men. Instead, the score of depression in men slightly increased at one-year follow-up, with a significant change in anxiety after MMR, but not at one-year follow-up. These findings indicate that men did not maintain the psychological improvement that was shown after MMR; instead, there was a tendency that they were slightly more depressed at follow-up. An earlier study investigating gender differences in chronic WAD patients showed small differences in men and women regarding psychosocial factors but found that women reported significantly higher social companionship and emotional support in problem situations . It is pn = 1468) showed significantly reduced interference after discharge and at one-year follow-up [The interference with activity was significantly reduced in both gender groups at one-year follow-up. A previous study on patients with disabling pain who underwent an MMR program (ollow-up . This isollow-up . Howeverp = 0.001) in a study by Angst et al. [In our study, pain intensity was significantly reduced for all patients, in line with some previous studies of MMR on patients with WAD, Sterner et al. (2001) reported decreased pain intensity, coping ability with pain and control of it at six-month follow-up . Similart et al. . Thus, tThere is an overrepresentation of women with conditions of chronic WAD and women with chronic pain are overrepresented in specialist clinics in Sweden compared to the community prevalence . More thOne of the strengths of our study is the self-assessments, which are included in the SQRP and are reliable and validated measures for WAD patients ,32. The The main limitation of the study is that no randomized control group was used and thus it is hard to eradicate conclusions of random effects on the course of treatment effects. Although the sample of patients were representative for participants in MMR during 2009–2015, another limitation is the high rate of non-respondents, 161/322 (50%) with 58.4 % of all the male respondents being in this group. The considerable majority did not complete at follow-up and this may have affected the results. A significantly lower score of physical health and more anxiety and depression was seen in this group which could explain their reason for not completing the questionnaire. A problem to be considered, which is also pointed out by Hurwitz et al. (2009), is the risk of biased conclusions on the effectiveness of MMR on patients with WAD and their specific interventions as it is difficult to extract results of certain interventions from other interventions embedded in multimodal packages combined in previous studies reviews . In addiThis study has implications for clinicians. Due to the complexity of WAD, the present study indicates that a five-week MMR program could be beneficial for patients with subacute to chronic WAD on physical and mental health, anxiety and depression, pain intensity and activity. Further controlled studies are needed to provide better knowledge of the long-term effects of MMR in WAD patients with a design that enables a more precise observation of what favorable factors there are in MMR, both in general and for each gender group. Specific instruments for WAD such as the Neck Disability Index could be used.


Currently, there is no standard therapy for treatment of acute renal colic. With the increased scrutiny and controversy now surrounding opioids, the authors identified a need to investigate an alternative medication for pain control. As such, they sought to determine the efficacy of sub-dissociative  doses (0.3 mg/kg) of ketamine in providing Emergency Department (ED) patients acute pain management for renal colic secondary to nephrolithiasis.After institutional review board (IRB) approval, the authors conducted a non-blinded, prospective clinical study. A convenience sample of n = 34 patients from the ED of a Western Michigan-based health system with suspected renal colic received one intravenous dose of ketorolac, 30 mg if over 50 kg body weight or 15 mg if under 50 kg In patients weighing greater than 50 kg, up to two doses of sub-dissociative ketamine were then given to further control pain. Pain was assessed at times 0, 30, 60, 90 and 120 minutes.There was a statistically significant pain reduction with administration of sub-dissociative ketamine, with 24 (69.2%) patients reporting an average reduction in pain score > 30% . Initial average pain scores for patients receiving sub-dissociative ketamine averaged 7.76 (SD = 2.55) on the 11-point verbal Pain Numeric Rating Scale. After a first dose of ketamine, patients’ average pain score was 3.56 (SD = 0.74) at 30 minutes. After two hours, patients’ average score was 2.56 (SD = 0.65), indicating that pain control was still effective over time with no statistically significant change in pain scores. Additionally, there was no statistically significant difference in pain reduction observed between genders .Based on these results, sub-dissociative ketamine may be considered a reasonable and effective supplemental non-opiate treatment option for suspected renal colic in otherwise healthy 18-70-year-old patients and could provide an effective alternative to traditional therapies. Further studies utilizing this methodology with larger, more generalizable samples are needed to further validate these findings. Renal colic is an acute, severe, intermittent pain caused by a stone obstructing flow of urine in the genitourinary tract. Lodging of a stone within a ureter increases the hydrostatic pressure causing the urothelium to stretch and activate afferent autonomic pain fibers. These fibers originate from the Thoracic 10 through Lumbar 1 vertebrae levels resulting in known viscerosomatic reflex referred pain patterns to the flank, abdomen, groin, and/or genitalia.Treatment opinions vary between providers, sources, and facilities. Steinberg et al. found that only 69% of renal colic patients received adequate analgesia while in the ED.Most evidence suggests non-steroidal anti-inflammatories are superior for analgesia with fewer side effects compared to opioids.During the past decade, SDK adjusted by patient weight (<1.0 mg/kg) has been recognized as an effective treatment option for acute pain for a variety of situations such as: wound dressing for burns, perioperative pain, cancer, chronic regional pain syndrome, abscess incision and drainage, limb fractures, closed reductions, and trauma.The purpose of this clinical, prospective study was to determine the efficacy of utilizing SDK 0.3 mg/kg IV as an analgesic agent for renal colic in a convenience sample of ED patients. The authors’ hypothesis for this trial was that use of SDK would provide an effective supplemental non-opioid option for the treatment of acute renal colic in the ED with minimal adverse side effects.This community-based study was a non-blinded prospective study testing the efficacy of an IV SDK dose of 0.3 mg/kg for the management of acute renal colic associated with nephrolithiasis in two EDs at a West-Michigan based health system. Before the study, the authors’ institutional review board approved the study protocol. Patients were enrolled upon written agreement using an approved informed consent according to institutional policy. This study was conducted in the Mercy Health ED campuses at the Hackley and Mercy facilities in Muskegon, Michigan. Combined, these campuses provide care to greater than 100,000 patients annually. The study population included a variety of ethnicities and ages. Enrollment period began in July 2016 and ended in February 2018.A convenience sample of eligible patients was obtained by board-certified emergency physicians, physician assistants, and emergency medicine residents using a standard renal colic protocol at the two ED study sites. Patients were offered participation based on clinical suspicion of nephrolithiasis after presenting with signs and symptoms of renal colic such as (but not limited to) flank, abdominal, groin or genital pain with nausea, vomiting, hematuria, and/or dysuria.Inclusion criteria were: patients of all genders, race, and ethnicities between the ages 18-70. Exclusion criteria included: history of ketamine abuse, pregnancy, prior admission for kidney stones in the past 90 days, contraindications to study medications, severe respiratory disorders, schizophrenia, renal impairment, peptic ulcer disease, and recent gastrointestinal or intracranial hemorrhage. Patients who satisfied all study criteria were counseled utilizing an IRB approved informed consent document.After consent was obtained, patients weighing greater than 50 kg received IV ketorolac 30 mg for analgesia (IV ketorolac 15 mg was administered if patients weighed less than 50 kg). At 30 minutes, pain was assessed using the 11-point verbal pain Numeric Rating Scale (NRS).If patients were still experiencing pain after 30 minutes of the initial SDK dose, a second IV SDK dose was offered. After 90 minutes, if patients were still experiencing pain at an NRS score of 5 or greater, or requested additional medications, pain management was then implemented at the discretion of the ED provider. IV Midazolam 0.1 mg/kg was also available for patients who experienced anxiety or agitation. The data collection for each sample patient ended at time of their discharge from the ED. There were no follow up evaluations required. Discharge medications were left to the discretion of the treating provider.Data were recorded using a paper data sheet with a patient identifying sticker. These data sheets were kept in the patients’ charts until all data collection was complete. Providers were asked to record vital signs, time, dosage, verbal pain NRS and any side effects experienced by patients. The data was de-identified by our lead investigator author (JG) when all data were collected and recorded. The de-identified data sheets were then placed in locked and collection boxes kept in the ED. These boxes were periodically emptied by study team members and manually uploaded into the Research Electronic Data Capture (REDCap) software for storage and future statistical analyses.The primary outcome measured was pain management after IV ketamine 0.3 mg/kg. Pain was assessed using an 11-point verbal pain NRS on a 0 to 10 scale. Pain scores and vital signs were measured at times 0, 30, 60, 90 and 120 minutes. Secondary outcomes measured included any adverse side effects.t tests and paired t tests to compare between intervention groups, and among initial relief of pain for ketamine with two-hour follow-up pain levels, respectively. All statistical analyses were carried out using the IBM Statistical Package for the Social Sciences (SPSS) version 25Initial descriptive analyses were performed examining overall mean pain NRS scores for each intervention group, as well as among gender subgroups. Descriptive statistics were also generated for the number of recorded adverse events. Further analyses were carried out utilizing independent A total of n = 34 patients were enrolled in the study. Eight (23.5%) of these patients were given IV ketorolac with adequate pain relief and thus not requiring ketamine. A sample subgroup 26 (76.5%) patients were administered IV ketamine. There were n = 14 (41.2%) male subjects in the study, and n = 20 (58.8%) female subjects. Previous studies have established a 30% reduction in pain can be considered a clinically significant threshold for demarcating pain improvement.Our primary endpoint was therefore to determine whether SDK met or exceeded this pain reduction goal. Overall, n = 23/34 (67.6%) of sample patients reported to have a clinically significant reduction in their pain score (> 30%). Of the patients who received SDK, n = 18/26 (69.2%) of study participants had a reduction in pain score > 30%. After receiving ketamine, pain was reduced from an initial mean pain score of 7.62/10 at time 0, to a pain score of 2.44 (SD = 0.78) at 30 minutes. (Table 2)t testing determined that these findings were significant, with a t = 3.16 and a p value = 0.004. In addition, the effect size for this difference was large, at 1.16 (95% CI 0.36 – 1.94). This suggests that not only did a large proportion of the patients receive benefits from IV ketamine in pain relief (n = 23/34 (69.2%), but also that the magnitude of pain relief conferred by receiving ketamine was substantial for this group.Patients who did not reach the authors’ observed 30% or higher pain reduction threshold had a mean pain score after 30 minutes of 6.88 (SD = 1.17). Independent t test analyses further revealed that this difference in 30-minute pain scores between the genders was not significant, with t = -1.047 and p = 0.306. This pain reduction was more pronounced two hours after receiving IV ketamine with mean pain for male participants of 2.38 (SD = 1.56) and a mean pain for female participants of 2.65 (SD = 0.65). Similarly, paired t test analyses revealed the difference in pain NRS scores two hours after the initial dose of IV ketamine was not significant across genders, t = -0.192, p = 0.850. (Table 3)We were unable to identify any statistically significant difference in reduction of pain NRS scores between genders. The average initial pain NRS score reported by patients who received IV SDK was 8.14 (SD = 0.63) for men and 7.50 (SD = 0.61) for women. The 30- minute pain scores in these groups were 2.63 (SD = 1.35) for men and 4.33 (SD = 0.91) for women. Independent The most common adverse event experienced by sample patients was dizziness (17.5%), followed by feeling “high” (10.0%), and “drunk” (5.0%). Similar symptoms were found in previous studies examining IV SDK with reports of dizziness, nausea, and emesis.Although our study was not adequately powered to examine the efficacy of IV ketorolac in pain reduction for renal colic, we did note a 30% or greater pain reduction with ketorolac alone in three of eight (38%) of patients. Initial average pain NRS scores in this group were 9.2 out of 10 which decreased to 6 out of 10 after receiving ketorolac. These findings were not, however, statistically significant . It is interesting to note that similar pain reduction has been documented in prior studies examining IV ketorolac for treatment of pain associated with renal colic.Our results demonstrate that SDK can be a viable therapeutic alternative to traditional treatment of renal colic in an ED setting. Several investigators have demonstrated the efficacy of low dose ketamine for a variety of patients presenting with pain complaints in the ED.Ketamine is a non-competitive antagonist at n-methyl-d-aspartic acid (NMDA) receptors with additional activity at mu opioid receptors. NMDA receptors are ligand-gated channels in the brain and spinal cord that bind the excitatory neurotransmitter glutamate. Current research suggests NMDA receptors are involved in pain transmission and modulation.Ketamine has fewer side effects  than current analgesic medications used to treat renal colic. Most ED physicians avoid use of ketamine for fear of side effects, most notably emergence phenomenon featuring post-sedation hallucinations and agitation. Studies have found these events are dose-dependent and are unlikely to occur at sub-dissociative ketamine doses less than 1.0 mg/kg.The use of NSAIDs has been limited in patients with renal insufficiency, pregnancy, and history of gastrointestinal bleed, hence the reason alternatives are necessary for patients with renal colic. In contrast, with increasing doses, opioids can also cause life threatening respiratory depression and delirium.Our sample size, though adequately powered for statistical analysis, was small. This makes us wary of a Type II Error that might otherwise be disproven in a larger sample size. Our results also displayed large standard deviations for a portion of mean pain NRS scores, which might have been further narrowed  in a larger sample. Likewise, our results were generated from a relatively small geographic area with a relatively homogenous patient population. Our enrollment criteria encompassed a wide range of ages .With a larger data set, further subgroup analyses stratified by age and gender might yield additional information to determine the ideal patient groups most appropriate for use of this medication. The prior administration of IV ketorolac may have contributed to decreases in pain after the patient had received ketamine as ketorolac has a duration of action of four to six hours. Future study groups may wish to investigate the utility of ketorolac and ketamine as monotherapy during inferiority / superiority studies as compared to opioid medications.In summary, our results indicate that IV SDK can be effective at treating pain associated with renal colic at 30 minutes and up to 120 minutes. Larger multicenter prospective studies are needed to confirm our results and ensure that they are generalizable to other ED settings and patient groups. We hope that these study results provide the basis for an expanded analgesic option in the acute management of renal colic. It behooves emergency physicians to consider non-opioid analgesia options in the midst of the current opioid epidemic and there is growing literature to support the use of SDK for acute pain management.The review of this manuscript was coordinated by SMRJ Chief Editor William Corser.The authors declare no conflict of interest.


BackgroundWith the recent advancement in medicine there has been a great emphasis on the management of chronic pain which remains as one of the major contributing factors for functional limitation in patients as well as a financial burden on healthcare. Newer treatment modalities are aimed at terminating the vicious pain cycles and in this regard peripheral nerve blocks have proven to be very effective.ObjectivesThe aim of this study is to evaluate the effectiveness of interventions for both cancer and non-cancer patients by objective assessment of the patients before and after the procedure.Materials and methodsThe study included 252 patients who underwent nerve block procedures in Shaukat Khanum Memorial Cancer Hospital from December 2016 to December 2018. The patients were evaluated using numerical rating scale (NRS) for pain, reduction in analgesic doses and patient satisfaction after one and four weeks post procedure. The data was analyzed using mean values and calculating percentages.ResultsIn cancer group, 168 patients were included; mean age 50.49 ± 15.39 with 46.43% females and 53.57% males, the average pain score was 2.62 ± 1.87 post procedure compared with 6.30 ± 1.87 post procedure. 48.21% of the patients reported a reduction in analgesia while 51.79% of the patients kept on using the same analgesics doses. 74.40% of the patients were satisfied and 25.60% patients remained unsatisfied after one week whereas 66.07% were satisfied, 23.81% were not satisfied and 10.12% loss to follow up after four weeks. In non-cancer group 84 patients were included; mean age 56.49 ± 15.79 with 41.67% females and 58.33% males, the average pain score before intervention was 5.99 ± 1.21 and after intervention it was 2.43 ± 1.62. In 73.81% non-cancer patients the analgesics doses were reduced and 70.24% patients were satisfied while 29.76% were unsatisfied after one week. After four weeks 55.95% were satisfied, 22.62% were not satisfied and 21.43% loss to follow up.ConclusionThe study showed decrease in pain scores in both group of patients and the importance of nerve blocks as an effective method for chronic pain management. The reduction in the use of other analgesics was also commendable in both the groups. With the recent advancement in medicine there has been a great emphasis on the management of chronic pain which remains as one of the major contributing factors for functional limitation in patients and poor quality of life as well as a financial burden on healthcare. The prevalence of chronic pain is estimated to be 37.3% in developed and 41.1% in developing countries [In 2012, there were more than 14 million diagnosed cancer patients and it is estimated that it will rise to more than 20 million by 2025 [Similarly non-cancer chronic pain is very common and its prevalence was estimated to be 19% in Europe . The AmeIn the past few decades, the mainstay management for chronic pain was opioids and topical therapies. World Health Organization (WHO) also recommends use of opioids as part of the analgesic step-ladder approach but prolonged use of opioid medication is associated with serious side effects and patient compliance is an issue. Recently, researchers are focused towards discovering the changes that happen in brain and nervous system because of chronic pain to better understand the physical basis and to establish better treatment options. Newer treatment modalities are aimed at terminating the vicious pain cycles and in this regard nerve blocks have proven to be very effective.Previously an abstract was presented which showed the efficacy of interventional pain procedures for cancer and non-cancer pain . The primary objective of this study is to emphasize the role of interventional procedures along with the pharmacological therapy in pain management.In this study, retrospective data of patients was analyzed who underwent interventional pain procedures at Shaukat Khanum Memorial Cancer Hospital and Research Centre from December 2016 to December 2018. The data was collected after getting Institutional Review Board (IRB) approval. The patients were evaluated using numerical rating scale (NRS) for pain , epidural rhizolysis (40) and intrathecal neurolysis (30) in cancer patients. Coeliac plexus block is carried out in patients with intractable pain in pancreatic and upper abdominal organ carcinomas. Recently a study was published which emphasized on the efficacy of these blocks for upper abdominal cancer pain . Most ofIn epidural rhizolysis the nerves carrying sensation to the spinal cord are desensitized by using a combination of local anaesthetic and steroid so that pain sensation is reduced. Epidural injections have been carried out since 1900s for relieving back pain. The efficacy of this procedure in reducing pain is well established in patients with refractory cancer pain , 16. At The procedure for intrathecal neurolysis was first described by Dogliotti in 1931 and has been used since then for intractable cancer pain. Careful selection of the patients is needed as some serious complications are associated with the procedure. The chemical neurolysis had been carried out with different agents including alcohol and phenol-glycerol combination with similar pain relief results in patients -19. LikeFor non-cancer pain intra-articular injection (32), epidural rhizolysis (32) and ganglion impar blocks (6) were the most common procedures. Musculoskeletal pain is the most common type of chronic pain seen in the adult population. In US adults the prevalence of doctor-diagnosed arthritis was 21% (46.4 million persons) . The paiGanglion impar block (GIB) was first described in 1990 and was primarily used for pain control in cancer patients. Since then the procedure is commonly performed for pain in the terminal segment of the spine near the coccyx and perineal area also referred to as Coccydynia. The blockade of nociceptive and sympathetic fibers is achieved by this block which helps in pain relief . VariousPain interventional procedures showed much better pain control and patient satisfaction in both cancer and non-cancer group as compared to conventional pharmacological therapy. Interventional procedures can be used as an adjuvant to pharmacological therapy and also will help in reducing opioid dose and their side effects.


Regional anesthetic techniques have become a vital part of the perioperative pain control process. The opioid crisis remains a major obstacle in the medical field today and many practitioners have looked upon regional nerve blocks to decrease opioid usage. The erector spinae plane block (ESPB) has gained prominence as a viable option for perioperative pain control for numerous procedures. Spinal surgery, although mostly utilized to relieve back pain, can be extremely painful for the patient perioperatively. To mitigate pain, many practitioners have turned to oral analgesics as regional techniques have not been typically employed. Anterior cervical discectomy and fusion (ACDF) surgeries in particular have been implicated as exquisitely painful and may predispose patients to sustained opioid use postoperatively. Many of these patients are on chronic opioid therapy and they have developed the syndrome of opioid abuse hyperalgesia; therefore, decreasing the need for opioids postoperatively is of utmost importance. We present the case of a successful ESPB performed prior to emergence for a patient undergoing ACDF to limit opioid consumption. Informed consent was provided by the patient for this case report. One of the greatest fear patients have when they come for surgery is pain. Postoperative pain control is of utmost importance to improve a patient's chance of a successful recovery and potential discharge from the hospital. Anesthesiologists play a vital role in the perioperative pain control process. Regional anesthetic techniques have been demonstrated as crucial to control pain after surgery and limit opioid consumption. One technique in particular, the erector spinae plane block (ESPB) has been shown to help with pain after breast, thoracic, and abdominal surgeries . It has A 67-year-old African American male with past medical history of benign prostatic hypertrophy and erectile dysfunction presented for C6-T1 ACDF due to cervical radiculopathy. An ESPB block was performed intraoperatively. Prior to emergence from anesthesia, the patient was placed in the lateral decubitus position. Using sterile technique and ultrasound guidance, a single shot ESPB was performed bilaterally at the T1 level. A sterile ultrasound probe was utilized to visualize the fascial planes. Using an in-plane approach the probe was placed vertically at the T1 level and the transverse process was initially identified. The transverse process can be seen as a "squared off" structure deep to the fascial planes. Next, a 4 cm 21-gauge stimuplex needle was introduced and the transverse process was initially contacted and the needle withdrawn superficially. The fascial plane was hydrodissected in a caudal direction and the injectate was administered. Initially, 40 mL of 0.2% ropivicaine was mixed with 10 mg of preservative-free dexamethasone and 50 mcg of dexmedetomidine (Dex-Dex). Some 20 mL of the Dex-Dex solution was deposited in the erector spinae plane on each side for a total of 40 mL administered. After the block, the patient was successfully extubated and transferred to the postanesthesia care unit (PACU) in stable condition. In the PACU he reported 2/10 pain and required no opioids. He had neither motor deficits nor hemodynamic instability. He had no difficulty swallowing solids and acknowledged numbness over the C3-T3 region. Over the course of the next three days he reported his pain as 0/10. He required no pain medications until postoperative day 4, on which he required oxycodone 5 mg - acetaminophen 325 mg once in the morning and once at night. At this time, sensory blockade began to diminish, though he reported no further opioid use in the subsequent days. As reported by the patient, his sensory blockade lasted about four days.The ACDF surgery, although routinely performed by many spinal surgeons, is a technically demanding procedure with rare but serious complications including respiratory insufficiency, dysphagia, and recurrent laryngeal nerve injury -6. TheseEnhanced recovery after surgery (ERAS) protocols have been instrumental in curbing perioperative opioid use throughout the nation. Regional anesthetic techniques are one of the mainstays of these regimens providing multi-modal analgesia for surgical patients. The ESPB is a viable and valuable addition to the anesthetic plan for ACDF surgeries that could be a part of ERAS protocols for these operations in the future. Further large studies are needed to assess the safety and efficacy of the ESPB for ACDF.