Complex regional pain syndrome type I (CRPS-I) is characterized by sensory, motor and autonomic abnormalities without electrophysiological evidence of a nerve lesion.Aims were to investigate how sensory, autonomic and motor function change in the course of the disease.19 CRPS-I patients  were examined with questionnaires , motor and autonomic tests as well as quantitative sensory testing according to the German Research Network on Neuropathic Pain at two visits .CRPS-I patients had an improvement of sudomotor and vasomotor function, but still a great impairment of sensory and motor function upon follow-up. Although pain and mechanical detection improved upon follow-up, thermal and mechanical pain sensitivity increased, including the contralateral side. Increase in mechanical pain sensitivity and loss of mechanical detection were associated with presence of ongoing pain.The results demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease, for which ongoing pain seems to be the most important trigger. They further suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion. In conclusion, this article gives evidence for a pronociceptive pain modulation profile developing in the course of CRPS and thus helps to assess underlying mechanisms of CRPS that contribute to the maintenance of patients’ pain and disability. Complex regional pain syndrome (CRPS) is characterized by sensory, motor and autonomic abnormalities , 2. Two To date the chronological sequence of somatosensory as well as motor and autonomic abnormalities with differentiation between examination of signs and symptoms in the course of the disease has been poorly studied. Additionally, a limitation of the few studies that evaluated the change of clinical abnormalities in the course of CRPS following treatment is that they used different diagnostic criteria and outcomes and mainly performed retrospective analyses of cases or used a cross-sectional study design .Thus, the aims of this study were to investigate if and how somatosensory, autonomic and motor signs and symptoms change in the course of the disease. This might help to determine whether loss of detection in CRPS-I is due to a nerve lesion or pain-induced hypoesthesia. Within this study we could demonstrate that patients with CRPS-I show a sensitization of the nociceptive system in the course of the disease. Furthermore, this study's results suggest that measured loss of function in CRPS-I is due to pain-induced hypoesthesia rather than a minimal nerve lesion.The study examined 19 patients with CRPS-I of the upper extremity. Recruitment consisted of all patients with CRPS type I of the upper extremity who had been included into the database of the German Research Network on Neuropathic Pain in Kiel, Germany between 2004 and 2007  (n = 45)A diagnosis of CRPS-I and inclusion into the database was made when (A) a glove-like distal distribution of pain, signs and symptoms that spread beyond the innervation territory of a single nerve was present, (B) Budapest criteria for clinical diagnosis were fulfilled  and (C) Patients with any neurological comorbidity that could otherwise influence testing results such as polyneuropathy, diabetes, vascular disease etc. as well as patients with skin lesions or dermatological disorders in the areas to be tested or with difficulties in German language skills were excluded from the study.The study was in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of the Faculty of Medicine at Christian-Albrechts-University of Kiel. All patients gave written informed consent to take part in the study.). At the beginning of the follow-up visit, patients were asked for presence of any new medical issues that might have occurred since the first examination. Afterwards, all patients received the different questionnaires and anamnesis was taken including questions regarding course and treatment of the disease, status of current pain as well as presence of inflammatory, sensory, autonomic and motor abnormalities for evaluation of symptoms. Next, a clinical-neurological examination was performed to screen for new comorbidities that might have developed in the meantime and could interfere with testing results. Then, quantitative-sensory testing (QST) was executed [The initial visit’s (visit 1) dataset was provided by the database of the German Research Network on Neuropathic Pain. The examination of both the initial visit and the follow-up visit was performed in a quiet room with a constant temperature of 21°C and included an anamnesis with a detailed assessment of subjective symptoms, a clinical examination with an assessment of objective signs, different questionnaires and quantitative-sensory testing (QST). Both examinations followed an identical algorithm with the exception of assessment of sleep disturbances, impairment of daily life and the ability to work as well as Quick-DASH , long-term skin temperature measurement and finger tapping, which were not part of the database of the German Research Network on Neuropathic Pain and were therefore only assessed upon follow-up  for presence of sleep disturbances and social retreat due to CRPS as well as their ability to work. Subjective estimation of disease improvement/aggravation was evaluated by the patients using a numerical rating scale (NRS) between -10 and + 10 representing worst aggravation and best improvement, respectively. Impairment of daily life due to CRPS was estimated on the NRS with 0 = no impairment and 10 = the maximum impairment imaginable. Mild impairment was defined NRS 0–3, moderate 4–6 and severe 7–10.Although it is often questioned whether CRPS type I represents a neuropathic pain entity, clinical experience and our former research  suggest Upon first and second examination, patients completed the German versions of LANSS . The LANThe NPS  was compThe German version of the MPI , 21 was Impairment of motor function was investigated with the Quick DASH . For evaCurrent and mean pain intensity during the week prior to examination was measured with a NRS . The character of pain as well as other sensory symptoms were assessed using a multiple-choice list of descriptions including choices for continuous, intermittent and/or orthostatic pain, lancinating pain, pain during movements and no pain (spontaneous pain) as well as presence of pain upon cold and/or warm exposure, touching the skin or slight pressure on the finger joints, presence of pricking or tingling, numbness and/or increased pain perception upon slightly painful stimuli.Subjective impairment of motor function was assessed using a multiple-choice list of descriptions including choices for presence of reduced muscle force, joint stiffness, impaired use of function, muscular atrophy, involuntary tremor or malposition (dystonia) of the affected extremity as well as use of extremity only possible under vision. Quantification of function impairment was performed using the task-specific scale : PatientPatients' perception of the presence of different autonomic symptoms was assessed using a multiple-choice list of descriptions including choices for presence of changes of complexion and/or hair growth, warmer/colder extremity compared to the contralateral extremity, continuous/intermittent edema, increased/decreased sweating and accelerated/decelerated nail growth.All patients were examined in the most painful area on the affected and corresponding area of the contralateral hand. Quantitative sensory testing (QST) was performed according to the protocol of the German Research Network on Neuropathic Pain which has been described in detail by Rolke et al. . The pro2) was compared to a single pinprick stimulus of the same force and defined WUR. WUR was not calculated if the first (single) stimulus was rated NRS 0/100 in more than three assessments, and in this case was handled as missing data. MDT was tested with standardized von-Frey-hairs  exerting a force between 0.25 and 512 mN. VDT was measured using a Rydell-Seiffert tuning fork . DMA was assessed using three different stimuli: a cotton wisp, a cotton wool tip fixed to an elastic strip and a soft brush and the subjects were asked to rate the pain on a 0/100 NRS.In short, thermal detection and thermal pain thresholds were analyzed using a thermode  with a baseline temperature of 32°C. To obtain thresholds, the temperature of the thermode was set to increase or decrease at 1°C/s and was terminated when the patient pressed a button. To examine PPT, a spring-loaded pressure threshold  was applied to the thenar with a slowly increasing stimulus ramp (50 kPa/s). For assessment of MPT and MPS, pinprick stimuli with fixed stimulus intensities  were used. MPT describes the threshold for pinprick pain, MPS indicates whether hyper- or hypoalgesia exists in the suprathreshold range. The perceived magnitude of pain to a series of pinprick stimuli  present on physical examination were recorded.Skin temperature was assessed manually on the testing area as well as on the finger pulps in digits one through five with an infrared thermometer . For skin temperature of the finger tips the mean of the five measurements of each hand was taken.Upon follow-up, long-term skin temperature was assessed for at least 8h and during the night with small loggers affixed to the small fingers of both hands. Loggers measured temperature every min . The small finger was chosen in order to reduce influences of movement or activities of fingers on skin temperature. Analysis was made according to Krumova et al. . Mean anIn order to quantify severity of CRPS, the CRPS severity score was used. This score is a measure to summarize the different clinical symptoms that characterize CRPS  into a clinically feasible severity score . Higher data base) / SDdata base). Z-scores above “0” indicate hyperfunction, i.e. patients are more sensitive to the tested parameter compared to controls (lower thresholds), whereas Z-scores below “0” indicate hypofunction and therefore a loss of or lower sensitivity of the patient compared to controls (higher thresholds). Both, z-values out of the 95% confidence interval  and a difference of more than two standard deviations in the z-scores between affected and contralateral extremity  were considered as abnormal. Wilcoxon test was used for calculation of intragroup differences between test and contralateral side as well as between first and second measurement. Linear relationships were assessed with Spearman’s rank test. Single tailed Chi2-test was used to test whether abnormal values were more frequent in patients than in healthy controls. P < 0.05 was considered statistically significant.Statistical comparison of QST data was made to a reference data base of healthy controls . All pat 7 (36.8%) patients had a left-sided, 12 (63.2%) a right-sided CRPS. In 8 (42.1%) patients, 3-phase-bone-scintigraphy was performed with a characteristic result for CRPS [No patient had abnormalities besides residues of CRPS upon neurological examination. Characteristics of patients are shown in for CRPS . Most coTable 3). Two patients (10%) reported worsening, one (5%) no change, but 16 (84%) subjective improvement of symptoms since first assessment (mean improvement 5.4 ± 5.5 NRS). Although CRPS severity score improved on follow-up examination compared to first assessment , only two patients (10%) reported no impairment of daily life, whereas all other patients still suffered from mild , moderate  or even severe  impairment of daily life. Approximately one fourth (26.3%) of patients was still unable to work.Mean time between visit 1 and the follow-up examination was 36 ± 10.6 months (range 16–53 months). In contrast to first assessment, Budapest criteria were only fulfilled by 13 (68.4%) of patients on follow-up examination . At the first examination 17 patients (89%) and at the follow-up examination 12 patients (63.1%) had a score ≥ 12 suggesting that neuropathic mechanisms are likely to be contributing to the patients’ pain.In one patient, NPS was not available. 12 patients (66.6%) demonstrated a reduced total score in NPS upon follow-up, whereas in five (27.7%) NPS total score increased. Overall, there was a trend towards a reduction of NPS total score upon follow-up examination compared to first visit . In particular, a decrease of felt pain intensity for heat , unpleasantness  and superficial pain  was described. The other parameters including pain intensity for pricking, dullness, cold, sensitivity, itching, or deepness did not differ between the two measurements.Upon MPI less disability  as well as an improvement of social activity  and daily in-  and outdoor  activities were reported in follow-up compared to first measurement. Social support  as well as punishing response  were less on follow-up compared to first visit, whereas solicitous response increased .Quick-DASH was not available for the first visit. Only one patient showed normal Quick-DASH values upon follow-up ; 6.82 for males (55–64 years). Mean Quick-DASH score upon follow-up examination was 41.4 ± 5.2 (range 4.6–75) suggesting considerable impaired function of the affected upper extremity.Table 3). Current and mean pain intensity during the last 7 days were reduced in follow-up compared to first examination .At the follow-up examination, 16 patients (84.2%) still reported presence of pain, although the number of patients with continuous pain was considerably lower compared to the first examination , whereas the number of patients with intermittent pain was higher . Compared to subjective reported symptoms, the frequency of mechanical allodynia upon QST was considerably lower at both examinations whereas frequencies for thermal and mechanical hyperalgesia were higher or showed a trend towards higher values upon QST compared to subjective reported symptoms (Table 3).Frequencies of positive and negative sensory signs and symptoms are shown in Table 4). Frequency of mechanical pain sensitivity for blunt pressure decreased, but increased for pinprick stimuli in follow-up examination compared to visit 1. 12/19 patients (63%) demonstrated an increase in sensitization for at least one thermal or mechanical pain stimulus (Table 5). Mechanical pain sensitivity (MPS) on the affected extremity was higher, the higher mean pain intensity  and the higher CRPS severity score  at follow-up examination were.Increased sensitivity for painful thermal and mechanical stimuli as well as dynamic mechanical allodynia and PHS on the affected side was more frequent in CRPS patients compared to controls during visit 1 and follow-up examination (Table 4). In contrast to the affected side, cold pain sensitivity of the contralateral side was more frequent in follow-up examination compared to visit 1 (Table 4). Furthermore, there was a trend towards increased frequencies for heat and mechanical pain  upon follow-up.On the contralateral side, a higher frequency for increased sensitivity to painful thermal and mechanical stimuli as well as paradoxical heat sensitivity (PHS) compared to healthy controls was observed in the follow-up examination, but not upon visit 1 (Table 4). Besides an increase in ipsilateral sensitization between visit 1 and follow-up, this contralateral increase in sensitization for at least one painful thermal or mechanical stimulus was observed in 12/19 (63%) of patients  and mechanical pain  were the most frequent. Sensitivity for cold pain  and mechanical pain  on the contralateral extremity were higher, the higher the CRPS severity score at follow-up examination was. Similarly, wind-up ratio on the contralateral extremity  was higher, the higher the NPS sum score at follow-up examination was. Thus, overall, increase in sensitization of both, affected and contralateral extremity was associated with a stronger impairment due to CRPS. Interestingly, it was independent from subjective improvement (Table 5).While frequencies for abnormal values upon heat and mechanical pain sensitivity (MPS), hyperalgesia to blunt pressure (PPT) and dynamic mechanical allodynia (DMA) were higher on the affected extremity compared to the contralateral extremity upon visit 1 these differences assimilated upon follow-up. Patients seemed to sensitize in the course of the disease resulting in increased frequencies of abnormal values for thermal and mechanical pain also on the contralateral side (Table 4). On follow-up, however, abnormalities for thermal and mechanical detection were less frequent, but still more common in CRPS than in healthy controls (Table 4).As already observed by Gierthmühlen et al. (18), loss of detection for thermal and mechanical stimuli was more frequent on the affected extremity in CRPS compared to controls upon visit 1 and follow-up ((Table 4) and frequencies for painful and non-painful thermal and mechanical loss did not differ between visit 1 and follow-up on the affected extremity.With the exception of loss of sensitivity to blunt pressure stimuli, hypoalgesia to thermal or mechanical stimuli was not very frequent in both visit 1 and follow-up Table 4). Furthermore, mechanical hypoalgesia to blunt pressure (PPT) and pinprick (MPS) was more frequent on the contralateral extremity compared to healthy controls (Table 4).Loss for thermal and mechanical detection on the contralateral extremity upon visit 1 was not as frequent as on the affected extremity, but loss for vibration detection on both visits as well as for warm detection upon follow-up were more frequent compared to controls (Table 5). In 3 of these patients, the contralateral side was affected. 6 (31.5%) patients showed normalization of mechanical and/ or vibration detection thresholds. Despite this improvement, 5 of them had a stable or only minimally improved loss of thermal detection. Loss of detection was independent from subjective improvement or CRPS severity score.Loss for mechanical, but not vibration detection was more frequent on the affected compared to the contralateral extremity upon both visits. Similarly, loss for cold detection and thermal sensory limen was more frequent on the affected extremity upon visit 1. Although not as obvious as for gain, a bilateral loss of detection was observed in 7 (36.8%) patients. 5 (26.3%) demonstrated an increasing loss of detection in follow-up compared to visit 1 with thermal detection thresholds being more affected than mechanical detection thresholds , patients without a pain reduction demonstrated more severe loss of warm detection , but less sensitivity to heat pain .When patients were grouped into those with ongoing or intermittent pain at follow-up examination, patients with ongoing pain showed higher mean pain intensity  and mechanical pain sensitivity as well as a stronger loss for mechanical detection on the affected extremity. Somatosensory profiles of patients with intermittent and ongoing pain are shown in Fig 2. Compared to healthy controls, CRPS patients were characterized by an increased sensitivity for heat (p < 0.05) and pressure pain (p < 0.01) as well as increased warm and mechanical detection thresholds (p < 0.05) on the affected extremity supporting findings by Gierthmühlen et al. (18). No differences compared to healthy controls were observed on the unaffected contralateral extremity.The somatosensory profile of the affected and corresponding contralateral extremity is shown in Fig 2).Cold and mechanical detection thresholds (MDT) as well as sensitivity for heat and mechanical pain to blunt pressure, pinprick (MPS) and dynamic mechanical allodynia were increased on the affected compared to the corresponding contralateral extremity . Also, thermal detection thresholds showed a trend towards an improvement. Interestingly, however, patients showed an increase in pain sensitivity to cold and pinprick  stimuli, whereas sensitivity to blunt pressure (PPT) decreased. This increase in pain sensitivity for thermal and mechanical stimuli, but not for blunt pressure was also observed on the contralateral extremity .Upon follow-up, loss of mechanical detection (MDT) on the affected extremity improved . Whereas patients described a worsening of motor symptoms such as reduced strength, decreased range of motion and stiffness of joints upon follow, the particular motor signs seen by the examiner did not worsen, but even tended to improve (Table 3). However, the mean number of finger taps was 32.6 ± 14.6 on the affected extremity (76.5% of unaffected side) and 42.6 ± 15 on the unaffected extremity upon follow-up suggesting a persisting impairment of motor function.For the presence of motor symptoms subjective description of patients was compared to the objective inspection of the examiner. Most frequent reported motor symptoms upon first visit were reduced strength in 10 (52.6%), decreased serviceability in 13 (68.4%), followed by stiffness of joints and decreased range of motion in 6 (31.6%) patients. Consistent with the abnormal Quick-DASH results functional impairment was rated 4.3 ± 2.4 (range 1–10) on the NRS upon follow-up. Overall, central motor symptoms such as dystonia and tremor were rare symptoms upon both visits. Muscle atrophy was a motor symptom that was only observed upon follow-up  or follow-up  examination.However, long term skin temperature measurement upon follow-up revealed a pathological increase of cold phases in three (21.4%) patients  and warm phases in one (7.1%) patient  leading to a significantly colder / warmer affected extremity, respectively. Intra-individual correlations and temperature oscillations between affected and contralateral extremity were decreased in 9 (64.3%) and 4 (28.6%) patients, respectively.Table 3. The most frequent symptom and sign on first visit was an edema (Table 3). While edema at rest was the most frequent sign and symptom upon visit 1, an intermittent edema was the most frequent form of edema upon follow- up.Other autonomic signs and symptoms are summarized in Table 3). Hyperhidrosis was more frequent than hypohidrosis upon first visit and follow-up. Increased or decreased growth of finger nails was described more frequent upon first visit (57.9%) than upon follow-up . Hypertrichiosis was a rare sign and symptom on both examinations.The frequency of sudomotor abnormalities decreased in the course of the disease (Table 6). The most frequent analgesics used during the entire treatment of CRPS were NSAID in 11 (57.9%), antidepressants (tricyclics) in 10 (52.6%) and anticonvulsants  in 10 (52.6%) patients. Interventional treatment was used in 8 (42.1%) patients. Patients who received only one kind of treatment did not differ from patients with different kinds of treatment with regard to pain, presence of hyperalgesia upon QST or subjective improvement (Table 6).Approximately half (47.4%) of the patients received a multimodal treatment with a combination of physiotherapy, transcutaneous electrical nerve stimulation, psychotherapy, interventional or pharmacological treatment, the other half was treated with oral pharmacotherapy only (47.4%) and one patient (5.3%) received a single interventional therapy (The present study shows that in the course of the disease (A) CRPS-I patients have an improvement of pain, sudomotor and vasomotor functions, but an ongoing impairment of sensory and motor function still leading to an impairment of daily life activity, (B) demonstrates that despite an improvement of pain and function patients with CRPS show a sensitization of the nociceptive system including the contralateral side and (C) suggests that loss of function in CRPS-I is due to central plasticity induced by activation of the nociceptive system i.e. pain-induced hypoesthesia.A systematic review of cross-sectional as well as pro- and retrospective studies has shown that vasomotor and sudomotor symptoms of CRPS tended to be the most common in the early stages of the disease and were the most likely to resolve . The preWhile sudomotor and vasomotor symptoms tended to improve, long-term follow-up studies have found that motor dysfunction, sensory symptoms and mild pain persisted in CRPS-I . The curWhile most patients still experienced pain at follow-up, its frequency was reduced from continuous to intermittent pain and it was less likely to be triggered by movement or orthostatic conditions with only four patients still needing ongoing pain medication. This reproduces the findings of two previous prospective studies that have measured fairly low pain intensity in CRPS upon follow-up examinations , 34. DesConditioned pain modulation is one well-known endogenous nociceptive modulatory mechanism. It is mediated by the subnucleus reticularis dorsalis in the caudal brainstem and leads to a generalized inhibition of nociceptive spinal cord neurons as a reaction to a painful stimulus , 39. AccIn contrast to thermal and other kinds of mechanical pain sensitivity, pain sensitivity to blunt pressure decreased upon follow-up. It has been proposed that an increased sensitivity to blunt pressure might mirror pathomechanisms of deep-somatic tissue . SupportWe observed a very strong decrease of pain sensitivity to blunt pressure on the affected and contralateral extremity upon follow-up compared to first visit . Although the clear trend of a reduction of pain sensitivity to blunt pressure is obvious, the extent of the reduction on both extremities might indicate a measurement error due to a too fast increase of pressure application upon follow-up. Nevertheless, this does not affect the main results of this study.LANSS, NPS and MPI showed an improvement of sensory symptoms and functionality in the course of the disease. Interestingly, the majority of patients had a LANSS score ≥ 12 at both visits suggesting that neuropathic mechanisms are likely to contribute to the patients’ pain. Moreover, patients showed mean NPS scores of 42.6 and 33.4 at the initial and follow-up visit, respectively, and therefore described distinct pain qualities associated with neuropathic pain . FurtherIt is possible that despite the absence of a major nerve lesion, the patients’ initiating event lead to a minimal nerve injury, which could not be detected in electrophysiology , but indRather, the observed association between reduced pain intensity and concomitant improvement in thermal and mechanical detection suggests that loss of function is due to central plasticity induced by activation of the nociceptive system as it has been shown in clinical and experimental pain, that is, pain-induced hypoesthesia –55.When interpreting the results it has to be kept in mind that signs and symptoms of CRPS are often dynamic, i.e. change due to external or internal factors such as pain, environmental temperature, posture, movement etc. This can be a possible explanation for the observed difference between signs and symptoms and influences frequencies of abnormalities. Furthermore, it is probable that patients who completely recovered from CRPS type I will be less likely to take part in the experiment than those who still have symptoms and would like to help researchers to improve knowledge and treatment of CRPS. Therefore, we believe that a selection bias could be an important limitation for the presented results. This study aimed to investigate residues of CRPS in a follow-up after a long time of disease duration. To investigate the fast changes that occur in the course of the disease, further examinations are necessary that repeat investigations in shorter intervals.In conclusion, results suggest central plasticity i.e. pain induced hypoesthesia as underlying mechanism for loss of function in CRPS-I. CRPS-I patients show an improvement of pain and autonomic function in the course of the disease but still a great impairment of sensory and motor function. Furthermore, CRPS-I patients show a sensitization of the nociceptive system including the contralateral side even after successful pain treatment. This sensitization was associated with higher mean pain intensity and the presence of ongoing pain, again indicating central plasticity as one underlying mechanism in CRPS-I.S1 Protocol(PDF)Click here for additional data file.S2 Protocol(PDF)Click here for additional data file.


Complex regional pain syndrome (CRPS) is a chronic, intensified localized pain condition that can affect children and adolescents as well as adults, but is more common among adolescent girls. Symptoms include limb pain; allodynia; hyperalgesia; swelling and/or changes in skin color of the affected limb; dry, mottled skin; hyperhidrosis and trophic changes of the nails and hair. The exact mechanism of CRPS is unknown, although several different mechanisms have been suggested. The diagnosis is clinical, with the aid of the adult criteria for CRPS. Standard care consists of a multidisciplinary approach with the implementation of intensive physical therapy in conjunction with psychological counseling. Pharmacological treatments may aid in reducing pain in order to allow the patient to participate fully in intensive physiotherapy. The prognosis in pediatric CRPS is favorable. Musculoskeletal pain is the most common reason for referral to pediatric rheumatologists. Causes of chronic musculoskeletal pain include a wide variety of inflammatory or non-inflammatory conditions, such as arthritis, hypermobility, fibromyalgia, growing pains, complex regional pain syndrome (CRPS) and more. Amplified musculoskeletal pain syndrome (AMP) is a generic and descriptive term used to describe chronic pain syndromes of unconfirmed etiology, such as fibromyalgia and CRPS. In AMP, pain signals are amplified, thus mildly painful or non-painful stimuli are registered by the body as very painful, and this leads to a functional disability – as the patient tries to avoid the induction of pain.In this review we will focus on the condition of pediatric chronic peripheral pain, more commonly referred to as pediatric complex regional pain syndrome (CRPS). Various nomenclature are used to describe this condition, including complex regional pain syndrome (CRPS), reflex sympathetic dystrophy, reflex neurovascular dystrophy, causalgia, and localized idiopathic pain. Matles was the first to describe a case of reflex sympathetic dystrophy in a child .CRPS is a condition of chronic peripheral pain, usually of a distal extremity. This syndrome is characterized by spontaneous or stimuli-induced pain, which is amplified to a very high visual analog scale (VAS) score, disproportionate to the actual incident trauma/stimulus, in the presence of a wide variety of autonomic and motor disturbances. CPRS is divided into two types. CRPS type I, previously known as reflex sympathetic dystrophy, usually develops after a preliminary event; usually minor a trauma or fracture, without any significant nerve injury. In contrast, CRPS type II, which is very rare in childhood, previously named causalgia, is induced by partial injury of a nerve or one of its major branches . This reAmong the pediatric population (children under 18 years of age), CRPS type I is more common among girls. The mean age at diagnosis is around 12 years of age. The lower extremity is more commonly involved than the upper, with some reports stating a predilection towards involvement of the foot –6.Information regarding the epidemiology of pediatric CRPS type II is wanting. There are case reports of CRPS type II among children as young as 3 years of age –9.Currently, there are no data available regarding the incidence of pediatric CRPS.The specific causes of CRPS are unknown. There is a general paucity of studies among the pediatric population regarding the etiology and pathogenesis of CRPS, although a variety of studies among adult patients present interesting hypotheses. However, the pathogenesis of pediatric CRPS is not necessarily identical to that of adult CRPS.In many cases, CRPS follows a relatively minor trauma, usually a sprain, twist, dislocation or soft tissue injury. In some cases, no previous injury was recalled –6, 10–13Stress has an important role in inducing or perpetuating CRPS. Cruz et al. found that children with CRPS showed generally intact cognitive function. However, they demonstrated an elevated risk of somatic symptoms and emotional distress, especially anxiety . These fChildren with CRPS find school more stressful, commonly due to a tendency toward over achieving or to learning difficulties, and tended to have more school related problems , 18. AbsSeveral studies have found a higher tendency towards a recent history of stressful life events among children with CRPS , 18, 19.The literature suggests several neurological mechanisms for CRPS, such as central sensitization and alterations in the central nervous system (CNS) and small fiber changes . In centSmall fiber changes have been suggested as a mechanism of CRPS . AcquireAlexander et al. suggested that activation of the immune system plays a role in CRPS pathophysiology. They compared plasma levels of cytokines, chemokines, and their soluble receptors among 148 CRPS adult patients to 60 age-matched, healthy controls. The subjects with CRPS were found to have significant increases in plasma cytokines and chemokines levels, and their soluble receptors as compared with controls . SimilarA study performed in the Netherlands among 52 adult CRPS patients found a significantly higher seroprevalence of Parvovirus B19, especially with CRPS of the lower extremity. However, no direct connection was found between CRPS and a previous infection, with Parvovirus B19 or any of the other microorganisms screened in the study . There hLi et al. conducted a study among 115 adult orthopedic patients with CRPS-I who underwent successful sympathetic nerve blockade for pain relief. They found a statistically significant positive history of allergies among CRPS I patients (nearly 70 %), compared to the control group (34 %). They concluded that a positive history of allergy/hypersensitivity reactions might be a predisposing condition for CRPS . CurrentThere have been reports of familial occurrence of CRPS, though no specific inheritance pattern or gene has been discovered –40. SeveHigashimoto et al. described eight children from seven families that fulfilled the criteria for CRPS-I, and who suffered from functional/dysautonomic conditions. All the children met the established criteria for mitochondrial disease, with six of the seven families meeting the criteria for maternal inheritance. They concluded that mitochondrial DNA sequence variants might predispose children towards the development of CRPS-I and other dysautonomias .Pediatric CRPS patients display a variety of sensory and motor findings, which can be linked to altered response and lower threshold of the central, autonomic and peripheral nervous systems. Common clinical features include pain and higher sensitivity to painful and non-painful stimuli of the affected limb, autonomic findings, motor disturbances, and trophic changes (changes resulting from interruption of nerve supply) , 47, 48.All patients describe constant pain in the affected limb, even at rest. The pain increases with movement of the limb , 14, 47.Autonomic findings of the affected limb include swelling and edema, temperature changes , hyperhidrosis, changes in skin color, cyanosis and sensitivity to cold, and mottled, dry skin , 5, 47.With time, trophic skin changes ensue in the affected limb, such as a decrease or increase in hair and nail growth , 47.Different motor disturbances have been described among pediatric CRPS patients, such as weakness, dystonia, tremors, spasms and fasciculations , 48. AgrThe clinical diagnosis of CRPS is based on a thorough history and physical examination, with a meticulous neurologic assessment. It is important to rule out other possible causes for chronic pain, such as orthopedic, neurological and rheumatologic disorders Table . The hisBaseline laboratory tests include a complete blood count, blood chemistry, C-reactive protein (CRP), erythrocytes sedimentation rate (ESR), creatinine kinase and antinuclear antibody (ANA). Usually CRPS patients have normal laboratory values. Imaging findings are normal, however, if the duration of the disease is prolonged or the degree of disability is very high, imaging modalities can demonstrate osteoporosis due to disuse . A bone There is no gold standard diagnostic test for CRPS in the pediatric or adult population. Therefore, several diagnostic criteria have been developed. In 1994, the International Association for the Study of Pain (ISAP) proposed a new taxonomy and diagnostic criteria for CRPS type I and II Table  2]. How. How2]. As previously mentioned, the diagnosis of CRPS is a clinical one, based on a meticulous history and physical examination which includes a thorough neurologic assessment. The diagnostic criteria developed for the diagnosis of adult CRPS can further assist in the diagnosis of CRPS in children and adolescents. We recommend that all patients suspected of CRPS should also undergo baseline laboratory tests, including complete blood count, blood chemistry, CRP, ESR, creatinine kinase and ANA. When the history or physical examination arouses suspicion of an active thyroid disease, thyroid function test should be performed as well. It is also recommended to perform a plain radiograph (if not previously performed) of the affected limb to rule out any localized pathology to the bones, joints and surrounding tissue. Usually, no further diagnostic evaluations are needed if there are no abnormal findings in the initial diagnostic workup. However, if the initial diagnostic workup suggests a different diagnosis, such as infection, a rheumatic disease, or a malignancy, further laboratory and imaging test are needed.The primary goals for the treatment of CRPS are pain relief and the improvement of all domains of functioning; thus, improving the patient’s quality of life. The scope of therapy includes an intensive physical therapy program combined with cognitive behavioral therapy (CBT) intervention. This often contradicts the patient’s logic, where rest is considered as means of improving his or her symptoms. A Cochrane review published in 2013 on interventions for treating pain and disability in adults with CRPS concluded that there was a lack of high quality evidence for most CRPS therapies . In 2012Exercise and physical therapy (PT) are the main treatment cornerstones of all pediatric CRPS patients , 57. HowVery intense exercise programs have been found helpful for pediatric CRPS. For instance, Sherry et al. treated 103 children with CRPS with an intensive exercise program of up to 6 h daily, without the use of medication or nerve blocks, with a 92 % success rate. Among those patients, 49 continued follow-up for more than two years, and 88 % were still completely symptom free . A studyPsychological therapies are a mainstay in the treatment of pediatric CRPS, and are recommended as an integral part of the interdisciplinary treatment approach . Patientn = 138) or to a control group of internet-delivered education (n = 135). They were assessed prior to and immediately following treatment and at 6-month follow-up. Activity was increased from baseline to 6-month follow-up for the internet CBT group compared to control (p = 0.03). Additionally, sleep quality improved (p = 0.04) and parental help (p = 0.007) and protective behaviors (p = 0.001) decreased. This research opens the door to a possible widespread, easily accessible treatment modality for pediatric chronic pain patients.The use of the internet as a mode of delivery of psychological interventions for children and adolescents with chronic pain and their families is an important new development. A Cochrane review published in 2015 examined the yield of remotely delivered psychological therapies in managing chronic and recurrent pediatric pain . ConclusTo date, there are no specific pharmacological treatments recommended for pediatric CRPS and no large scale, clinical trials of any medications are being conducted.Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol are common over-the-counter medications; thus, they are readily available to patients when chronic pain symptoms first appear. There are reports of the use of NSAIDS or paracetamol as an adjunct to physiotherapy, mostly in order to facilitate the child’s participation . In a clAmitriptyline and phenytoin have been used in cases of pediatric CRPS, usually in addition to physical therapy and sometimes in combination with an antiepileptic drug, mostly gabapentin. Some patients reported improvement , 12, 70.There are few case reports describing the use of gabapentin for the treatment of pediatric CRPS patients , 71–73. Ketamine is an anesthetic with an analgesic effect; it is an NMDA receptor antagonist. It can cause psychomimetic side effects, which can produce delirium and hallucinations. There are studies among adult patients of the efficacy of ketamine infusions for CRPS –78. In aIn a recent review  of invasTo date there are no specific, large, prospective, blinded, placebo-controlled studies of invasive treatments in pediatric CRPS. There are, however, many case reports and small case studies on use of these treatment modalities. Invasive treatments for CRPS carry a risk of complications and the potential risks against the potential benefits should be considered carefully. To illustrate, a retrospective record review of 37 German pediatric CRPS patients, documented considerable polypharmacy, with each patient taking an average of 4.4 (range 1–10) medications at admission to a chronic pain inpatient program. In addition, 43 % of patients had undergone unsuccessful invasive pain treatments prior to admission, including at least 13 children who received two or more invasive treatments .Transcutaneous electrical nerve stimulation (TENS) is a noninvasive therapy method that uses low-voltage electrical current for pain relief. The use of this treatment modality has been described in the literature with regards to pediatric CRPS treatment , 84–86. In general, pediatric CRPS patients have more favorable outcomes compared to adults. Many will have spontaneous resolution after a few months. The multidisciplinary team approach combing PT and CBT will lead to remission in most children; however, relapses are common. In a study by Sherry et al. , of the Other reports concluded that the prognosis of pediatric CRPS is not as favorable as reported , 88. TanPediatric CRPS is a chronic pain syndrome that differs from the adult version. It is more common among adolescent girls and the distal lower extremity is most commonly affected. Symptoms include limb pain, allodynia, hyperalgesia, swelling and/or changes in skin color of the affected limb, dry and mottled skin, hyperhidrosis and trophic changes of the nails and hair. The exact mechanism is unknown, although many different mechanisms have been suggested. The diagnosis is clinical, with the aid of the current adult criteria for CRPS. A complete patient history and examination are needed with judicious laboratory and radiographic tests to rule out other possible causes. Once pediatric CRPS is diagnosed, the standard care consists of a multidisciplinary approach with the implementation of intensive physical therapy in conjunction with psychological treatment. Treatment should take into consideration the child and the surrounding environment, family, and academic and social issues. Pharmacological treatments may aid in reducing pain in order to allow the patient to participate fully in intensive physiotherapy. Invasive treatments should be reserved for refractory CRPS cases, after considering the benefits versus the risks in each case. With the current knowledge and an intensive approach, the prognosis in pediatric CRPS has improved considerably. Further studies are needed in order to develop better diagnostic tools, improve understanding of this syndrome, and improve treatment outcomes and lower recurrence rates.


The harvest of iliac crest bone grafts (ICBG) is associated with relevant donor site pain, but may be lowered by the application of lidocaine loaded on biodegradable, hemostatic putty for sustained local analgesic release. The goal of this double-blind controlled trial was to assess the efficacy of adding lidocaine to a hemostatic putty (Orthostat ™) to treat donor site pain following harvest of ICBG in foot and ankle procedures.After ICBG harvest during a foot and ankle procedure, the resulting bone defect was either filled with Orthostat™ (n = 7) or with the same hemostatic putty loaded with lidocaine . During the first 72 postoperative hours, donor site and surgical site pain were managed by patient controlled morphine delivery and a peripheral nerve block. Donor site pain was periodically quantified on a Visual Analog (VAS) and a Wong Baker FACES scale. Pain scores were plotted over time to calculate the area under the curve (AUC) to quantify the overall pain experienced in specific time intervals.Orthostat-L™ significantly reduced donor site pain over the first 12 hours postoperatively as evidenced by a significant decrease of the AUC in both VAS (p = 0.0366) and Wong Baker FACES pain score plots (p = 0.0024). Cumulated morphine uses were not significantly decreased with Orthostat-L™.The addition of lidocaine to a hemostatic putty offers a significant ICBG donor site pain reduction over the first 12 postoperative hours.NCT01504035. Registered January 2nd 2012.ClinicalTrials.gov The online version of this article (doi:10.1186/1471-2474-15-415) contains supplementary material, which is available to authorized users. Cortical autologous iliac crest bone grafts (ICBG) are widely used in orthopedic surgical procedures, such asPatients undergoing ICBG harvest often experience significant post-surgical bleeding and painThese considerations prompted the incorporation of lidocaine into a biodegradable hemostatic putty (Orthostat™ currently marketed as Hemasorb™) to locally provide anesthetic to the surgery site (Orthostat-L™). The Orthostat™ putty is composed of a polyvalent salt of a high molecular weight carboxylic acid, an alkyl benzopyranol ester and Vitamin E which enables a continuous release of lidocaine. Orthostat-L™ additionally comprises lidocaine at a concentration of 16% of its dry weight. In a previous in-vitro and animal study, lidocaine was released from the putty in a exponential fashion with a half-time of approximately 6–8 hours..With the addition of Lidocain to Orthostat, pain control may be provided by two mechanisms. The hemostatic component may decrease the formation of irritating subperiostal hematomas, while the continuous release of lidocaine may decrease pain perception at the periosteal level.In animal studies, the application of Orthostat-L™ resulted in a dose dependent, sustained analgesia in rats over a duration of two to three days with no evidence of systemic toxicity–23. HoweIt was the primary objective of this study to compare the analgesic effectiveness of a lidocaine loaded hemostatic putty (Orthostat-L™) with a lidocaine deficient putty (Orthostat™), defined as visual analog (VAS) and Wong Baker FACES scale outcomes, in a random sample of patients undergoing ICBG harvest for foot and ankle procedures. We hypothesized that the addition of lidocaine to the putty would provide significantly better pain control in the early postoperative period. For the purpose of this study, we defined “early postoperative” as an observation period of 72 hours during which we searched for differences in reported pain.As a second objective, we aimed to test if, after the administration of the lidocaine loaded hemostatic putty, peripheral blood licocaine levels would stay below the threshold for liver toxicity of 6 mg/l.This study was designed as a prospective, comparative, active-controlled, double-blind trial of the analgesic effectiveness of Orthostat-L™  with Orthostat™ (active control) in patients undergoing iliac crest bone graft (ICBG) harvest. The main outcome measurement was pain measured on a VAS and Wong Baker scale. We aimed at being able to detect an at least 10% ± 5% difference between two independent groups in the cumulative VAS scores within the early postoperative time period with a power of no less than 90% and a two-tailed alpha of 5% . This is consistent with an effect size of 2, thus requiring a total sample size of 14, or 7 per group, to reach a power of 90%. Such a sample size would still allow detecting a sample size of 1.5 without less than at least 80% power.From May to July 2008, we enrolled 14 patients undergoing foot and ankle surgical procedures with the use of a structural iliac crest bone graft. Patients who were between 18 and 71 years old and capable of completing a patient administered analgesia (PCA) device and who had given their written informed consent were included in the study. Patients with previous ICBG harvest, serious medical conditions including liver and heart failure, bleeding diathesis, hypersensitivity to lidocaine or to components of the hemostatic putty or any mental (dementia/psychiatric disorder) impeding their cooperation in the postoperative evaluations were excluded. Upon inclusion, patients were randomly allocated to the Orthostat™ or Orthostat-L™ group. There were seven patients in each group. Patients as well as all medical staff were blinded to which product the patient received.As a result of the random allocation, there were seven patients in each group. Table NCT01504035, registered January 2nd 2012) and approved by the local ethical committee (EKBB registry number 14/08).The study was conducted in accordance with the current version of the Declaration of Helsinki and under the laws and regulations enforced by the local ethics committees. This trial was registered in ClinicalTrials.gov  administered a peripheral nerve block in the popliteal fossa proximal to the surgical site. Blocks were performed with 20–30 ml of mepivacaine 1.5% and bupivacaine 0.5%. After injection a 20G catheter was inserted for continuous postoperative sciatic nerve block with ropivacaine 0.2%, using an elastomer pump with a flow rate of 6-10 ml/h.3). The graft dimensions were measured and the donor site was dried with sterile gauzes. Then either Orthostat™ or Orthostat-L™ was administered to the exposed bone surfaces under firm digital pressure until the level of material filling ICBG harvest site was flush with the bone surface. The amount of Orthostat™/Orthostat-L™ was determined by the number of 2 g portions applied to the harvest site and by weighing the leftover of the last portion used. The time from the end of putty application to complete hemostasis at the donor site was recorded and judged to be complete when there was no active bleeding noted by the surgeon. In addition the aspirated blood volume from the iliac crest was measured and recorded for blood loss. The wound was then closed in layers. No blood drain was inserted at the iliac crest harvest site.Upon exposure and preparation of the primary surgical site at the foot and ankle, the same surgeon (VV) obtained an iliac crest bone graft in the following manner. A skin incision was made over the anterolateral aspect of the iliac crest. The aponeurosis of the external oblique was exposed and incised. The iliac crest was exposed subperiosteally, and a tricortical ICBG was obtained with an oscillating saw. The size of the graft was adapted to the structural defect at the foot and ankle to be bridged but was not larger than 3 cm × 1 cm × 2 cm  was calculated to represent the Additional postoperative pain control was provided for all patients using patient controlled analgesia pumps (PCA) loaded with morphine. The cumulative dose of morphine used within the first 72 h after surgery was quantified.. The formation of a local hematoma at the iliac crest harvest site was assessed by ultrasound performed after 48–72 hours. After discharge from the hospital, patients were followed up at 14 and 30 days after surgery. During these follow-up visits, any adverse event such as prolonged pain, hematoma, herniation etc. at the pelvic harvest site was recorded.Serum lidocaine levels were measured after the administration of the peripheral nerve bloc (baseline) and at 2, 4, 8 12, 48, and 72 hours after the application of the putty using high performance liquid chromatography. Blood samples for serum lidocaine measurements were obtained from the basilic vein of the ipsi-contralateral arm and analysed immediatelyTwo-tailed t-tests for independent samples were used to compare cumulative PCA, bleeding time, total blood loss, and graft size across treatment groups. Continuous variables including VAS pain scores at different time points as well as the area under the curve for VAS and Wong Baker scores were tested using repeated measure ANOVA. For the 16 hours’ time point, more than 20% of VAS and Wong Baker FACES measurements were missing and thus the time point had to be dropped. Discontinuous variables including Wong - Baker scores were analysed using Fisher’s exact test with Bonferroni adjustments for multiple measurements. Results are given as mean ± SD. An alpha of 5% was considered significant. All analyses were done using intercooled STATA 10 .As shown in Table vas) as compared to Orthostat™ from 1 to 12 hours   of the VAS score  for the Orthostat-L™ group than the control group Figure .Figure 3There were no serious adverse effects experienced by subjects in the study. There was one case of seroma at the graft site in the intervention group that became evident prior to discharge on the fifth day after surgery. It required manual expression of the serous fluid to resolve. There were no complications in the control group (p = 0.2994).Iliac crest bone graft harvesting is associated with a donor site morbidity of up to 30%, 14, 16.Our study has potential limitations. Our sample was small, aiming for a between group difference of 10% ± 5%, and a larger study would be capable of detecting a smaller difference than that with statistical significance. However, the statistical significance of such a smaller difference must be put into relation with its clinical meaning, which might be questionable. Also, experiencing postoperative pain and response to analgesic medication has considerable inter-individual variability. Another potential shortcoming of a small sample size is a potentially higher risk of bias due to differential distribution. However, the enrolled patients were not significantly different in demographics and duration of procedure undergone, and systemic disease and lidocaine-related issues were exclusion criteria in our study. Hence it is not likely that our data are affected by substantial bias.. Our data do not suggest that the duration of pain relief was restricted by limited lidocaine release from the putty. Lidocaine levels remained elevated in the Orthostat-L™ group even beyond 36 hours which was in fact in line with previous in vitro results[In our study, Orthostat-L™ significantly reduced cumulative VAS and Wong Baker FACES pain scores at the harvest site within the first 12 postoperative hours. Thereafter, pain scores in the control group began to return to baseline values. Nonetheless, pain scores in the Orthostat-L™-group continued to be lower compared to the Orthostat™-group, however, without statistical significance. The limited duration of significant pain relief provided by Orthostat-L™ may be explained by the fact that the control subjects returned to low pain levels just after 12 hours and by 20 hours after putty administration. Thus, there was no relevant pain for Orthostat-L to mitigate after this time period. In addition, the effects of lidocaine could have been also been altered by a local inflammatory response due to the surgical intervention and, additionally, to the putty. It has been postulated that inflammatory cell released peroxynitrite could decrease the effect of local anesthetic effects, 27. Ouro results. Thus, Onot narcotic use. Second, Ip et al.[Throughout the study, we could not detect a significant difference regarding cumulative PCA use between the two study groups. This result may be interpreted in two ways: First, our study was primarily powered to detect significant differences regarding cumulative VAS scores and Ip et al. showed iOur data do not suggest that the duration of pain relief was restricted by limited lidocaine release from the putty. Lidocaine levels remained elevated in the Orthostat-L™ group even beyond 36 hours which was in fact in line with previous in vitro results. Thus, OIn terms of safety, our study was able to demonstrate that serum lidocaine levels remained well below the level of toxicity (6 mg/l). The maximum serum lidocaine level noted in our study was 2.1 mg/l and was registered after 4 hours. We noted the occurrence of one seroma in the Orthostat-L™ group. This complication may be rather interpreted as a minor donor site complication and not as an adverse event directly related to the local drug application. Such minor complications may occur with a frequency of 10-15%, 16.Previous studies have already suggested the installation of local anesthetics to reduce donor site pain at the iliac crest, 29–35. When comparing Orthostat-L™ with local anesthetics, it must be considered that that Orthostat-L™ is also a hemostatic agent. In contrast to local anesthetics, Orthostat-L™ may therefore additionally help to prevent irritating subperiosteal hematomas, which further contribute to donor site pain. Nevertheless, these speculations on the superior effectiveness of Orthostat-L™ to reduce donor site pain needs clarification in future randomized controlled trials.A bioresorbable hemostatic putty with lidocaine, as Orthostat-L™ has significant effectiveness in controlling pain experienced within 12 hours after iliac crest bone graft harvesting compared to a putty without lidocaine, as Orthostat™. We found no evidence for systemic toxicity or an increase in risk of adverse effect using a lidocaine based putty.Marc Andreas Müller and Arne Mehrkens first authorship.


Pain management is concerned with the reduction of suffering and enhanced quality of life rather than a reduction of pain complaint. Persistent pain may be associated with morbidity such as emotional distress, physical disability, and sleep disturbance. Despite the prevalence of pain in musculoskeletal disorders, effective first line treatments are not without moderate to severe side effects. The aim of this study is to compare the efficacy of clinical hypnotherapy with acupressure in reducing major unresolved chronic pain; brachial neuralgia.A randomized controlled clinical trial in University Malaya Medical Centre (UMMC) (MEC No: 937.11) was conducted between Dec 27, 2012 and June 20, 2014. A total of 12 patients with chronic brachial neuralgia were randomly assigned to hypnotherapy group or acupressure group. Four sessions of hypnosis were conducted approximately 1 week apart in hypnotherapy group and two sessions fortnightly in acupressure group. Patients were scored during one month pre-treatment, pre-treatment (week 0), mid-treatment (week 2), post-treatment (week 4) and 4 month post-treatment. Pain scores were obtained before treatment as a baseline and post treatment as outcomes using the Visual Analogue Score (VAS), Brief Pain Inventory, and SF36v2 Health Survey which measure overall health improvement and the efficacy of the treatment were used. The hypnotherapist used a standardized pain analgesic protocol throughout the sessions and tailored induction with specific analgesia suggestions according to patient’s need. Patients in acupressure group were guided by qualified acupuncturist on how to apply the acupressure patches to the meridian points. Patients were provided with 2 weeks supply of acupressure patches and reviewed after mid treatment week 2 for any revision of meridian points patching protocol.There was significant improvement (P=0.002) in the average pain intensity from pre-treatment mean score of 8.58 ± 1.51 (range 7-10) to post treatment 5.33 ± 2.23 (range 2-9) overall. Generally, there was 32.5% documented improvement in the pain score post-treatment as compared to pre-treatment. Hypnotherapy provided higher reduction of pain intensity of 35% (P=0.006) as compared to acupressure 30% (P=0.023) with mean score of pre treatment 8.67 ± 1.75 (range 6-10) to post treatment 5.17 ± 1.60 (range 4-8) and pre treatment 8.50 ± 1.38 (range 7-10) to post treatment 5.50 ± 2.88 (range 2-9), respectively. The comparative background variables between two groups were made on the basis of paired t-test and a non-parametric method, Wilcoxon sign rank test which was used to detect significance difference (P=0.027) and assess the efficacy of treatment between the two groups.At the 4 month follow up assessment, the mean of pain score in hypnotherapy group (5.83 ± 1.83) was still significantly lower than that in the acupressure group (7.16 ± 2.32).The majority of the patients had significant improvement in the pain intensity score except for 2 brachial neuralgia patients in the acupressure group. There was also improvement in pharmacotherapy usage (P<0.05) in terms of reduced dosage and frequency. 75% showed positive response in both treatment groups and were in favor to continue the sessions. The improvement in pain and disability score 4 months post-treatment for both groups were significantly reduced but significantly higher than the post treatment pain intensity indicating the chronic pain was successfully managed by the patient through self-hypnosis and acupressure carry over effect. The positive response to the majority of pain interference in the hypnotherapy group may be attributed to the effect of tailored suggestions accorded by suggested standardized protocol by our qualified hypnotherapists. We could not specifically determine the standard acupressure meridian point protocol for brachial neuralgia patients with neuropathic pain as the meridian points differed from patient to patient.The results suggest that both hypnotherapy and acupressure provide effective relief of average pain intensity with greater relief in the hypnotherapy group as compared to the acupressure group, in terms of pain intensity and disability score. The self-hypnosis was beneficial in term of long-term pain intensity reduction as well as quality of life. Findings in this study supported that both hypnotherapy and acupressure had the impact of improving sleep, enjoyment of life, general activity, work as well as controlling mood.


Percutaneous radiofrequency thermocoagulation of the trigeminal ganglion through the foramen ovale is a well-established procedure for the treatment of trigeminal neuralgia (TN). However, this approach can be tricky when individual trigeminal sub-branch nerve block is required. We report our initial experience of image-guided radiofrequency thermocoagulation of the maxillary branch through the use of foramen rotundum.From February 2012 to February 2015, we treated 25 patients with isolated TN of the maxillary branch. Radiofrequency thermocoagulation of the maxillary branch through the foramen rotundum was performed under fluoroscopy. TN pain was evaluated using the visual analogue scale both before and after the procedure.The mean preoperative visual analogue scale score was 8.6 ± 0.8. The pain completely disappeared after the initial procedure in 22 patients and after a second procedure in 2 patients. An additional patient had a postoperative visual analogue scale score of 2 and did not undergo further treatment. Facial numbness occurred in 23 patients but was tolerable. Patients were followed up for a mean of 14.74 months . Recurrence was observed in 9 patients (36%) during the follow-up period. All recurrences were well managed with repeat procedures.Percutaneous radiofrequency thermocoagulation of the maxillary branch through the foramen rotundum under fluoroscopy is a safe and effective procedure for the treatment of isolated TN of the maxillary branch. Typically, patients with TN are first treated with medications, including carbamazepine or oxcarbazepine. If the pain cannot be controlled using conservative treatments, surgical interventions are then usually considered.5Trigeminal neuralgia (TN) is a neuropathic disorder characterized by intense and distinctive pain in the distribution of one or more branches of the fifth cranial nerve. Diagnosis of TN is typically based solely on the patient's history and description of pain. Pain occurs in paroxysms, with each episode of pain lasting from a few seconds to several minutes with no pain experienced in between.6 However, histologic animal studies have indicated that the induced injury affects all sizes of nerve fibers, regardless of their myelination status.7 Therefore, the success of the procedure may rely on reducing the overall sensory input to the trigeminal root. Radiofrequency thermocoagulation through the foramen ovale can be a difficult and time-consuming procedure for both the physician and the patient, requiring very precise placement of the needle near the Gasserian ganglion. Failure to position the needle properly can lead to treatment failure, recurrence, or potentially serious complications that include, but are not limited to, nonspecific block, intracranial hemorrhage, and infection.10Percutaneous thermocoagulation of the branches of the trigeminal nerve and the trigeminal ganglion has long been used in the treatment of TN. One possible mechanism for this technique involves differential thermocoagulation of trigeminal rootlets, whereby the action potentials of nociceptive fibers (A-δ and C) are blocked at lower temperatures than those that transmit tactile sensation.We present our initial experience with percutaneous thermocoagulation of the maxillary branch of the trigeminal nerve through the foramen rotundum, similar to that first described by Huang et al in 2014, under the 3D fluoroscopic guidance in a series of 25 cases.From February 2012 to February 2015, 25 patients with isolated TN of the maxillary branch were treated with radiofrequency thermocoagulation through the foramen rotundum under fluoroscopic guidance at our hospital. Patients were all medically refractory and included 12 men and 13 women with a mean age of 64.4 ± 11.1 years (range: 26–82 years). The left side of the face was affected in 14 patients, whereas the right side was affected in 10, and 1 patient experienced bilateral symptoms. The disease course ranged from 1 month to 16 years  or recurrence of pain were included in this study. Patients with severe systemic disease, cardiac or pulmonary dysfunction, and/or secondary TN were excluded.This study was approved by the Institutional Review Board of Huaiyin Hospital of Huai’an City. Each patient has signed a written informed consent form.Approximately 30 minutes before surgery, patients were administered 1 KU of hemocoagulase  and 5 mg of morphine subcutaneously. Patients were placed in the supine position on an angiography table of a biplane fixed x-ray system with 3D capability  with the head fixed in a slightly extended position. The C-arm was adjusted into an anteroposterior projection, with the detector positioned caudally toward the affected side. With this positioning, the projection of the ipsilateral pterygopalatine fossa was inferior to the ipsilateral zygoma, posterior to the maxillary bone, and anterior to the coronoid process of the mandible  was inserted through the needle. The probe was stimulated with an initial pulse of 50 Hz. Patients experienced paresthesia in the distribution area of the maxillary branch at 0.2 V which intensified with increased voltage. No paresthesia was noticed in the distribution areas of the ophthalmic and mandibular branches at 0.7 V, indicating that the needle was correctly placed within the maxillary branch and not within the ophthalmic and mandibular branches. The position of the needle within the foramen was confirmed using 3D-reconstruction in the coronal, sagittal, and needle trajectory planes Fig. .After positioning of the needle was confirmed, the radiofrequency probe was removed, 0.3 mL of 2% lidocaine was slowly injected through the needle, and patients were monitored for 3 to 10 minutes until the pain along the maxillary branch was replaced by a feeling of numbness. The radiofrequency electrode was reinserted into the needle and thermocoagulation was performed at 75°C for 4 minutes. During thermocoagulation, functions of the ophthalmic and mandibular branches were repeatedly assessed by physical examination and patient feedback.11 Patients were shown a horizontal line marked from 0 (no pain) to 10 (most severe pain) and asked to rank the severity of their pain.The visual analogue scale (VAS), a widely used metric for measuring pain, was completed by patients both pre- and postoperatively.The mean preoperative VAS score was 8.6 ± 0.8. Of the 25 patients, 22 (88%) indicated a postoperative VAS scores of 0, indicating complete resolution of pain after the procedure Table . Of the Operative time was very short at an average of 15 minutes. Average puncture time (from insertion to placement) was about 5 minutes with an average radiofrequency time of approximately 4 minutes. Surgical complexity was similar to that of traditional percutaneous image-guided trigeminal thermocoagulation.1 Percutaneous treatment modalities for TN consist of balloon compression, glycerol rhizotomy, and radiofrequency thermocoagulation. All 3 treatments have been shown to induce pain relief by directed injury to the trigeminal nerve and are generally considered to be safe, efficient, and effective.12 Recent improvements in percutaneous radiofrequency thermocoagulation have involved improving the targeting accuracy of the procedure through the use of intraoperative computed tomography neuronavigation and frameless stereotactic cannulation of the foramen ovale, with good success.15Trigeminal neuralgia is a neuropathy involving intense pain limited to the distribution of 1 or more of the branches of the trigeminal nerve.16 described their experience with 54 patients and reported increased rates of long-term pain relief (85% vs 54% at 12 months and 62% vs 35% at 36 months) in the patients undergoing percutaneous radiofrequency thermocoagulation with navigation compared with the previously standard procedure. A later study by Yang and colleagues17 in 2010 involved 79 patients with TN who underwent radiofrequency rhizotomy. Yang et al reported no difference in surgical outcome or pain relief between CT-guidance with 3D reconstruction and fluoroscopy-guided groups. However, CT-guidance significantly decreased the median time for needle placement (14 vs 40 min) and intraoperative patient discomfort.Xu and colleaguesThe classic approach to radiofrequency thermocoagulation involves placement of the needle through foramen ovale. However, tracing the maxillary branch of the trigeminal nerve from its origin at the Gasserian ganglion involves passing through foramen rotundum to exit the cranium, subsequently crossing the pterygopalatine fossa, and entering the orbit through the inferior orbital fissure. Thus, an approach through the foramen rotundum, rather than the foramen ovale, has the potential to simplify targeted treatment of the maxillary branch of the trigeminal nerve in TN patients.4 and found that, compared to an approach through foramen ovale, thermocoagulation through foramen rotundum showed similar results for pain relief both immediately postoperative and at 1-year follow-up. In addition, approaching the trigeminal nerve through the foramen rotundum was associated with a shorter procedural time and fewer serious adverse effects including masticatory weakness and corneal perforation. All patients treated by Huang et al through foramen rotundum experienced some degree of facial numbness. However, while this group had a greater incidence of facial numbness than the foramen ovale group, their degree of numbness was typically less extensive.Huang et al proposed a computed tomography-guided technique through foramen rotundum to block the maxillary branch of the trigeminal nerve4—were observed. The vast majority of our patients (92%) experienced facial numbness; however, this numbness was considered tolerable and corroborates the findings by Huang et al that numbness caused by a foramen rotundum approach is typically not extensive or deteriorative to quality of life.In the present study, we performed a similar technique using 3D image-guided radiofrequency thermocoagulation of the maxillary branch through the foramen rotundum. No patient underwent more than 2 intervention procedures and all but 1 patient experienced immediate and sustained pain relief after initial or secondary treatment. Recurrence occurred in a minority of patients (36%), similar to that of comparable techniques. The complications observed following this technique were mild and usually did not require additional treatment. No incidence of masticatory weakness or corneal perforation—both known complications of radiofrequency coagulation through foramen ovaleThis series of 25 cases of TN of the maxillary nerve treated with 3D image-guided radiofrequency thermocoagulation through foramen rotundum demonstrates that this technique may help mitigate the risk of iatrogenic damage to the ophthalmic and mandibular nerves through repeated movements of the needle intracranially—which could result in weakened mastication and/or corneal damage. Furthermore, this technique may reduce the need for repeated intraoperative electrical stimulation and thus reduce patient discomfort. However, larger prospective clinical studies are necessary to determine the true efficacy of at this technique.


The problem of chemotherapy-induced peripheral neuropathy (CIPN) has risen to the forefront for oncology professionals, who must pay greater attention to this distressing and potentially debilitating adverse effect than they did in the past. This is because CIPN may occur and even be dose limiting after several frequently used antineoplastic agents, including platinum analogs , taxanes , vinca alkaloids , bortezomib (Velcade), and thalidomide . Chemotherapy-induced peripheral neuropathy may also lead to numerous negative effects on activities of daily living, functioning, leisure activities, dressing, household and work activities, going barefoot or wearing shoes, and driving . There is little direct evidence to support the use of adjuvant analgesics  in the CIPN setting, although many clinicians empirically use them based on other pain management principles.Our understanding of the possible mechanisms and progression of CIPN from different chemotherapy agents has increased, but it is far from complete. Other obstacles to managing CIPN include gaps in clinicians’ knowledge regarding recognition and grading of CIPN and the lack of universally agreed-upon, multidimensional, clinically relevant assessment tools that are also sensitive, reliable, valid, and easy to use . Furthermore, patients are often reluctant to report manifestations that might interfere with what they consider to be "life-saving" chemotherapy; there are few interventions to prevent, minimize, or treat CIPN.With these quandaries in mind, it is useful to review an article by Smith and colleagues entitled "Effect of Duloxetine on Pain, Function, and Quality of Life Among Patients With Chemotherapy-Induced Painful Peripheral Neuropathy," which was recently published in the Journal of the American Medical Association . As the authors of this notable paper point out, this is the first publication of a large phase III study that explored a potentially effective intervention for painful CIPN caused by platinum and taxane analogs. Also of note, Dr. Smith, the first author, is an oncology nurse scientist whose clinical and research interests include CIPN, neuropathic pain, and cancer survivorship.The authors of this article very clearly laid out in their research report the rationale for the study, the research questions, their primary and secondary endpoints, data analysis, and discussion of their findings. This approach allows the reader to "buy into" the conclusions the researchers drew from their study, which was designed to determine whether duloxetine—a selective serotonin and norepinephrine reuptake inhibitor (SNRI) antidepressant—would have usefulness in relieving neuropathic pain in adult cancer patients with confirmed CIPN. The strong study design and relatively large sample size were capable of generating trustworthy, clinically important information that supported the study hypotheses.A major strength of this multisite study was its design: prospective, randomized, double blind, and crossover . This is the type of research that can generate the highest-quality evidence upon which to base clinical decisions. The main hypothesis was that duloxetine would be superior to placebo to decrease pain after 5 weeks, in the first or the second treatment period. Secondarily, the study sought to assess the effect of duloxetine on quality of life (QOL), functioning, and adverse events.STUDY METHODSA total of 231 patients with any type and stage of cancer participated in this study. These patients had been treated at one of eight sites across the United States and were eligible to participate if they were at least 25 years old and the only chemotherapy regimen they had received included a platinum or taxane: oxaliplatin, cisplatin, paclitaxel, nanoparticle albumin-bound paclitaxel, or single-agent docetaxel . Eligible patients had CIPN confirmed by symptom history and symmetric stocking-glove numbness, paresthesias, or loss of deep tendon reflexes that started after receiving neurotoxic chemotherapy; at least grade 1 sensory pain ; and at least moderate  neuropathic pain for 3 or more months after completing chemotherapy.Patients were not eligible if they had received other neurotoxic chemotherapy agents, had received other chemotherapy before the neurotoxic agent, or were currently receiving chemotherapy. They could be taking analgesics  as long as their doses were stable  in the 2 weeks before they began the study, but they could not be taking agents known to affect serotonin levels. Patients with type 2 diabetes or peripheral vascular disease who had pain believed to be related to CIPN could participate in the study, but they were defined as "high risk." Equal numbers of high-risk patients were assigned to each treatment group to control for the potential confounding effect of comorbid illness on CIPN. p < .001). The actual toxicity of each patient who dropped out of the study was not provided, but Table 1 shows the grade 2/3 adverse effects experienced by at least 3% of patients in both groups.Random assignment of the 231 patients led to 115 patients in group A  and 116 patients in group B . However, 17 patients never received either treatment or did not provide data during the first treatment period, so 214 patients were evaluable. The dropout rate due to adverse effects in the initial treatment phase of the study was 11% for the duloxetine-treated patients but only 1% for the placebo-first group  to detect a 0.98-point change in average pain between the duloxetine and placebo groups. This was similar to calculations used in diabetic research on duloxetine.Patients received identical capsules containing either duloxetine or placebo. During the first week of each treatment period, they took one capsule per day (duloxetine 30 mg or placebo); in weeks 2 through 5, they took two capsules per day (duloxetine 60 mg or placebo), which were similar doses to those given in other studies of painful peripheral neuropathy . Weeks 6 and 7 were a washout period to allow for the excretion of duloxetine, which could influence responses in the second treatment period. The study schema is shown is Table 2.ASSESSMENTMeasures used to assess pain, peripheral neuropathy, and QOL were the Brief Pain Inventory Short Form (BPI-SF), the NCI CTCAE, and the Functional Assessment of Cancer Treatment, Gynecologic Oncology Group Neurotoxicity (FACT/GOG-Ntx) subscale . The change in average pain during the initial treatment period, the main variable of interest, was measured using the BPI-SF average pain severity item on the first day of weeks 1 and 6. Average pain severity was selected based on recommendations from the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) study . The investigators also measured the proportion of patients in both groups who experienced any decrease in pain and those who had clinically significant decreases in pain severity (30% or 50%).Pain interference with function and daily activities was measured by summing other BPI-SF items for a total interference score . The effect of CIPN on QOL was measured by the FACT/GOG-Ntx, which assesses numbness, tingling, and discomfort in the hands or feet; difficulty hearing; tinnitus; joint pain or muscle cramps; weakness; trouble walking or buttoning buttons; and agnosia . There were no published data defining a cut point for a clinically important change in the FACT/GOG-Ntx score, so the researchers defined a 2- to 3-point change as a clinically meaningful improvement in QOL. Patients completed the NCI CTCAE each week to assess adverse events and baseline and weekly sensory CIPN. Secondary endpoints in CIPN-related QOL were also measured by these instruments. Changes attributable to initial treatment were the differences between the week 1 and week 5 scores, and changes for crossover treatment used week 8 and week 12 scores. Analysis of covariance stratified by neurotoxic agent or risk of painful CIPN was used to test for any group effects during the initial treatment period on the primary and secondary endpoints.RESULTS p = .003), which was a moderately large effect size of 0.513 . As can be seen in Table 3, the 95% confidence intervals for duloxetine and placebo do not overlap. Changes in pain severity during the second (crossover) treatment period were also statistically significant and related to treatment , but this was not an order effect (p =.43). That is, it was not related to whether patients received duloxetine first or second. The mean difference in the change in average pain score between the groups was 0.73 (p =.003), similar to differences in studies that led to US Food and Drug Administration (FDA) approval of duloxetine for painful diabetic neuropathy, fibromyalgia, and osteoarthritis . Furthermore, more patients who received duloxetine (59%) had some decrease in pain than did placebo-treated patients (38%). Patients who got duloxetine were more likely to have clinically meaningful reductions in their pain (30% or 50%) than were those who got placebo . The authors concluded (based on the IMMPACT study recommendations) that 10% to 20% decreases in pain severity represent minimally clinically important findings, whereas a 30% change is a moderately important improvement and a 50% change is a substantially important improvement.The main results focused on measures at the end of the first treatment period, which are discussed (unless otherwise specified). Of greatest importance, the study found that the duloxetine-treated patients had a significantly greater decrease in average pain than the placebo-first patients . The researchers had defined the minimal clinically important difference in pain severity as a 0.98 difference in mean average pain severity between the treatment groups.Another potentially clinically useful finding was a suggestion that duloxetine might be more beneficial for patients with CIPN secondary to platinum analogs than to taxanes . As compared to placebo, the relative risk of experiencing a 30% reduction in pain with duloxetine in platinum analog-treated patients was 3.05 and that for a 50% reduction was 3.78, whereas the relative risk of a 30% pain reduction was 0.97 and a 50% pain reduction was 1.22 with duloxetine among taxane-treated patients (p =.01). The change in mean interference score for patients treated with duloxetine first was 7.9 vs. 3.5 for patients treated with placebo first. The mean difference between the two groups in mean change score was 4.40. Before starting the study, more patients who were taking other pain medications were assigned to placebo than to duloxetine: 43% vs. 31%. This difference held at the end of the first treatment period, when 36% vs. 29% were taking concomitant medications. However, 27% of patients in the duloxetine group compared with 19% of placebo-treated patients discontinued all medications by the end of the initial treatment period.At the end of the initial treatment period, as compared to placebo, duloxetine-first patients reported a greater decrease in pain that had interfered with daily functioning (p =.03). The mean change score difference between the groups was 1.58 (p =.03). Furthermore, 41% of patients who took duloxetine and 23% of patients who received placebo reported a decrease in numbness and tingling in the feet (not significant). The trend held through the second treatment period, and 41% of patients who crossed over to duloxetine vs. 21% of patients treated with placebo had improved hand numbness and tingling.The secondary study endpoints also favored duloxetine over placebo. Pain-related QOL improved more in patients treated with duloxetine than in those given placebo. Mean changes in the FACT/GOG-Ntx total score were 2.44 for duloxetine-treated patients vs. 0.87 for placebo-treated patients Adverse effects did not seem to be a major problem for most patients, although they may have led patients to discontinue treatment. There were no grade 4 (moderately severe) or 5 (severe) adverse effects in either treatment group, and the frequency of grade 2 (mild) events (16% in duloxetine-treated and 27% in placebo-treated patients) and grade 3 (moderate) events (7% vs. 3%) was similar. Fatigue, insomnia, and nausea were most common in patients treated with duloxetine, whereas somnolence, insomnia, and fatigue were the most common in patients treated with placebo.Smith and colleagues (2013) concluded that compared to placebo, 5 weeks of duloxetine was associated with a statistically and clinically significant improvement in pain and may work better for oxaliplatin-induced than taxane-induced painful CIPN. They also reminded readers that when thinking about clinical significance, they should consider treatment side effects, the rapidity of the drug effect, tolerability, and the treatment influence on other functions and QOL—all of which were positive in this study. On the other hand, the authors pointed out that the mechanisms of platinum- and taxane-induced peripheral nerve injury are different, which may explain why duloxetine seemed more efficacious for platinum-related than taxane-related neuropathic pain.The authors recognized several limitations of their study, including the imbalance in dropout rates due to adverse effects in duloxetine- vs. placebo-treated patients , even though the incidence of adverse effects was similar in both groups . They postulated that this might be partially related to the finding that more duloxetine-treated patients had grade 3 adverse events and also might have dropped out if they guessed which drug they were taking. Baseline pain determination may also have been a limitation; while oncology professionals typically use the NCI CTCAE or similar grading scales for CIPN to guide a focused history and physical examination and to grade CIPN severity, the researchers did not specifically train the examiners regarding CTCAE use because grading is "deeply embedded into oncology practice"  and the CTCAE has suboptimal interrater reliability and poor sensitivity to detect subtle changes.In reviewing research reports such as this one, a reader might think about whether it was ethical to include a placebo arm, as well as what the rationale was for comparing duloxetine to placebo at all. In addition, a reader may question whether to consider a relatively small statistically significant difference in decreased average pain scores when patients were taking duloxetine as clinically significant. And finally, should the recognized shortcomings of the CTCAE in assessing peripheral neuropathy accompanied by pain influence how we judge the study?INCLUSION OF PLACEBOThere is no ethical issue in comparing duloxetine to placebo because there is no "standard" treatment—another drug or combination with confirmed efficacy—for CIPN. If there were, the research would have used this as the comparison arm. In fact, there is scant research focused on CIPN and little prior data to support specifically using duloxetine for CIPN. Two small studies were done in Asia. One, a pilot study that included only 15 cancer patients with neuropathic pain, found that 7 patients (about 47%) experienced reduced pain with duloxetine at doses of 20 to 40 mg/day . The other study was a prospective, single-arm, open-label study that included 39 patients who experienced chronic CIPN after receiving oxaliplatin-based chemotherapy . Patients were scheduled to receive at least 12 weeks of duloxetine to assess its effectiveness on pain severity, neuropathic symptoms, and symptom interference with activity (measured by the CTCAE). In the first 3 weeks, 9 patients withdrew from the study because of adverse effects. Among the remaining 30 patients, 19 achieved ³ 30% pain relief. Of these, 9 had improved neuropathy.And why implement a study with a placebo arm at all if there is any other potentially useful drug—in this case, perhaps pregabalin—that has FDA approval for painful diabetic neuropathy? Numerous  studies have had "negative results," that is, a drug or compound is found to be no better than placebo, thereby preventing FDA approval of a new drug or use of an approved agent for a new purpose. Placebo arms, particularly in double-blind studies, have been important since Beecher, a renowned anesthesiologist, published his classic article proposing that placebos could improve or reverse various conditions in approximately 35% of patients . For instance, Chvetzoff & Tannock (2003) reviewed a total of 37 randomized, placebo-controlled studies of cancer patients and found that placebo treatment was associated with moderate rates of improvement in pain, appetite, weight, and performance status as well as rare to low (2% to 7%) tumor response.The point of the placebo arm is to separate out positive psychosocial influences  and expectations on treatment outcomes (placebo effects) from actual physical effects . Negative influences are called "nocebo" effects. The study of Smith and colleagues illustrates the power of the placebo effect: 38% of patients who initially got placebo reported some decrease in their pain, although the mean reduction was less than in patients who got duloxetine. Conversely, a placebo may be justified when the comparator drug has significant adverse effects . Patients in the Smith et al. study also experienced adverse effects, although more patients who got duloxetine than placebo dropped out of the study because of adverse effects. Similarly, Chvetzoff & Tannock (2003) found that toxicity or adverse effects occasionally led to treatment withdrawal from a placebo arm in studies of cancer patients.BENEFIT OF SELECTION BIASAnother interesting factor in the Smith et al. study is that the sample was limited to patients whose only previous chemotherapy included a platinum analog  or a taxane  and who were not currently receiving any chemotherapy (which might be increasing CIPN), which eliminated the problem of intervening variables. This "selection bias" was fortuitous in that it illustrated the fact that different mechanisms of CIPN may influence effective treatment measures . It also highlights the idea that taxane-induced CIPN is a larger problem than some clinicians realize. Thus, in clinical practice, one might opt to try duloxetine in patients with CIPN associated with a taxane or other agent. Unanswered questions for using duloxetine or any adjunct agent include when to start, how to escalate doses (and what maximum dose to go to), what dose-limiting adverse effects are most important to assess, what constitutes a "successful" analgesic response, and how long a time-limited trial should go on before changing to a different adjunct agent.IS IT PRACTICE-CHANGING?Regarding the statistically significant differences of duloxetine over placebo, one might question whether the differences in mean pain changes are large enough to influence clinical decision-making regarding prescribing duloxetine to treat painful CIPN. The answer is yes: 59% of patients experienced some decrease in pain after 5 weeks of taking duloxetine, and more duloxetine-treated patients decreased their opioid analgesic intake. While a relatively small difference in mean pain  ratings would not seem impressive if two opioid analgesics were compared for nociceptive pain, neuropathic pain is notoriously difficult to control. Neuropathic pain may be somewhat responsive to opioid analgesics, but dose escalations to relief of pain are not usually possible without causing distressing adverse effects. Prescribers often empirically add an adjuvant analgesic  to a patient’s analgesic regimen based on data in patients with other types of neuropathic pain.Smith and colleagues’ study adds weight to selecting duloxetine for CIPN, and even relatively modest decreases in pain may allow lower opioid analgesic doses. Furthermore, their study confirmed that some patients also experienced improved QOL secondary to reductions in the dysesthesia and paresthesia patients describe in their feet and hands (stocking and glove distribution). It would be valuable to learn whether longer-term use would lead to greater relief of pain and symptoms reflecting nerve damage.IMPROVEMENT OF ASSESSMENT TOOLSSmith and colleagues (2013) recognized the need to identify more clinically effective and not overly burdensome means to assess baseline and interval peripheral nerve function and damage than CTCAE items (Table 4), which are currently the best we have in oncology. The CTCAE construction was consensus based, and there are no data to support the reliability and validity of the tool or of individual items . Because the symptoms and severity of CIPN are largely subjective, recognition and grading are often difficult; comparing published studies is challenging because there is no universal standard for quantification of CIPN symptoms, and physicians tend to underreport CIPN incidence and severity . Furthermore, physicians, nurses, physician assistants, and patients are often unclear about the terms we have to describe neuropathic pain .It is worth noting that most assessment tools have been designed to measure neuropathy from other conditions  and have not been validated in patients with CIPN . One recent study confirmed that intraclass correlation coefficients of CTCAE items among triads of oncologists, oncology nurses, and patients were generally modest and might lead to questionable clinical decisions . Study participants rated 7 CTCAE items  within 68 minutes of each other, and analysis calculated correlation coefficients ranging from 0.50 (for constipation) to 0.71 (for neuropathy). Clinically feasible and useful assessment tools are clearly needed. To this end, Smith et al. (2011) published a preliminary assessment of a treatment and referral algorithm for CIPN that advanced practitioners can consider implementing. Readers can access this article directly by scanning the barcode on page 362 or using the link provided in the reference list.The work of Smith et al. (2013) discussed here represents a solid study and provides us with valuable data to improve the management of our patients with CIPN. It builds upon their previous research and supports the use of duloxetine starting with a dose of 30 mg/day and escalating to 60 mg/day in 1 week. Another strength is that this study clearly identifies its limitations and suggests other important clinical questions that still need to be answered. We can look forward to further enlightening research from Smith and colleagues.