It is unclear whether local anesthetic eye drops can be safely used for the topical anesthesia of patients with minor corneal injury who are discharged from the emergency department (ED).To assess whether topical 0.4% amethocaine self-administered to a maximum recommended frequency of once every hour for 36–48 h is safe in the management of uncomplicated corneal injury in patients discharged from the ED.A pilot randomized double-blinded trial comparing topical 0.4% amethocaine with topical normal saline.Forty-seven subjects were recruited, with 22 randomized to receive amethocaine and 25 to receive placebo . Baseline characteristics, including corneal injury type, were similar in both groups. There were no significant functional or clinical adverse sequelae in the majority of enrolled patients who could be contacted at 2 weeks (17/22 for amethocaine and 21/25 for placebo). Follow-up for the primary study outcome was suboptimal, with only 7/22 from the amethocaine group and 9/25 from the saline group presenting for 36–48 h review; there was a statistically nonsignificant trend for persistence of the corneal defect in the amethocaine group as compared with the saline group .Compared with saline drops, amethocaine eye drops are not definitely safe but they are effective for topical analgesia in minor corneal injury. Until further definitive studies, topical nonsteroidal agents or long-lasting artificial tears may be preferred for the topical analgesia of minor corneal injury. Return for corneal re-evaluation will necessarily remain suboptimal in an otherwise self-limiting condition, leading to a bias even if study recruitment is good. Corneal abrasion, with or without retained foreign body, is the most frequent ophthalmic presentation to an emergency department (ED). AlthoughTrials investigating the outpatient management of corneal abrasions suggest that topical ophthalmic preparations of non-steroidal anti-inflammatory drugs (NSAIDs) are effective for subjective pain relief and possess short-term safety. However, ED use of these agents is limited because the anesthesia achieved with topical NSAIDs, while statistically significant, did not reach clinically important levels when measured using visual analog pain scores in these trials; further,There is a therefore a need for a safe and effective method for managing the pain of corneal abrasions and ultraviolet keratitis. Ophthalmic topical anesthetics are known to provide excellent corneal anesthesia for 15–20 min, with return of normal sensation within 60 min.Despite its established role in facilitating assessment and instrumentation of the cornea during eye examination or surgery, there has been little research into the use of topical anesthetics in the outpatient setting and then only in post-surgical patients. When compared with placebo, local anesthetics have been shown reduce ocular pain without affecting corneal wound healing or visual performance in post-surgical patients for 24 h after hospital discharge.10 HoweveThere is no clinical trial data to suggest that a 1- to 3-day course of intermittent self-administered topical anesthesia would cause damage to the eye in the post-surgical setting. Several trials10 have dHowever, it remains unclear whether this safety profile in the post-surgical setting would extend to patients with minor uncomplicated corneal injury. Therefore, we conducted a study to assess whether use of topical anesthetics during the first 36–48 h after initial ED assessment of a corneal abrasion or ultraviolet keratitis reduces eye pain and increases patient satisfaction without a clinically significant delay in epithelial healing or other complications.We conducted a randomized double-blinded trial comparing self-administered topical 0.4% amethocaine with 0.9% saline solution in the outpatient management of uncomplicated corneal injury. The study received approval from the Mater Health Services Human Research and Ethics Committee and is registered with the Australian Clinical Trials Registry (ACTRN012605000273684).Recruitment occurred over 12 months at the Mater Adult Hospital ED, an urban ED with specialist ophthalmology services. For inclusion in the study patients had to have any one of the following: (i) traumatic superficial corneal abrasion(s), (ii) superficial corneal abrasion(s) with retained foreign body(s), or (iii) keratitis from welding flash exposure.Exclusion criteria included the following: more than 36 h elapsed since the event causing the corneal injury, patient less than 18 years old, history of adverse reaction to any local anesthetic agent or to any ophthalmic preparation, eye pathology  other than refractive error, contact lens use, current pregnancy or lactation, signs of conjunctival infection, functionally one-eyed, and patient requiring urgent referral to ophthalmology (including penetrating eye injury).Eligible patients were approached for informed consent .For the purposes of standardization, no patient in the trial was given cycloplegics nor was eye patching applied; otherwise, initial ED assessment and management was at the treating doctor's discretion.Data regarding corneal healing was excluded for patients presenting for review at < 36 or > 48 h after recruitment, which is less or more than the duration expected for re-epithelization. Patients with a rust ring requiring further instrumentation at 36–48 h review were also excluded from the statistical analysis since it would not be possible to determine whether the patient's symptoms were ascribable to the treatment he or she was allocated or to the retained foreign body.Mater research pharmacists not involved in the design or conduct of the study prepared identical, clear, minim packs of either 0.9% saline solution or 0.4% amethocaine solution. There were 6 batches, with each batch containing 16 randomly ordered mimim packs ; the batches were sent to the ED in no particular order. The mimim packs in the 6 batches were sequentially numbered from 1 to 96 (6 × 16 = 96). After the patient had given informed consent, he or she was given the next available minim pack, the composition of which was not known to either the patient or clinician. The patient was instructed to instill one drop in the affected eye(s) once hourly as needed for pain relief and to take oral analgesia as required. The containers were stored in a drug refrigerator.Data was collected at original assessment in the ED; during ED review 36–48 h after recruitment; in the form of a diary maintained by the patient recording visual analogue pain scores; and telephone follow-up interview 2 weeks after recruitment. Intention-to-treat analysis was performed for all outcomes.The primary outcome was healing of the corneal defect; potential delay in healing is the main concern with the use of outpatient topical anesthesia. We compared two independent proportions  of patients whose cornea had completely re-reepithelialized at 36–48 h. Complete re-epithelialization was defined as the absence of fluorescein stain uptake. Sequential analysis in the context of the triangular test was usedSecondary outcomes were assessed at the 2-week telephone interview; these outcomes included use of oral analgesia, unscheduled medical review, visual problems, and satisfaction with treatment received. A patient diary was used to record third hourly patient-rated pain perception; pain was measured using a visual analogue scale – an ungraded 100-mm horizontal line with the left end indicating “No pain” and the right end “Worst pain imaginable.” The patient was asked to apply a vertical mark on the line to indicate the severity of the pain. One of the investigators measured the distance in millimeters from the left (“No pain”) end of the line. Cumulative scores were a summation of up to 12 pain measurements over 36 h. A chi square comparison of two independent proportions for binary secondary outcomes  was performed. We used the Student's t-test to compare the difference between the mean cumulative pain scores in the two treatment groups.Power and sample size calculations were based on a two-tailed difference of 25–50%, as there has been a large variation in corneal healing rates in previous studies.15 This tBaseline characteristics were similar in the amethocaine and saline groups .There was a statistically nonsignificant trend for persistence of the corneal defect in the amethocaine group as compared with saline group (2/7 vs. 1/9) .At 2 weeks, the satisfaction with their management was similar in both groups and there was no significant difference between the groups in the amount of oral analgesia used for eye pain, in ongoing visual problems, or in the need for unscheduled medical review.Twelve of 22 patients (55%) allocated to the amethocaine group and 9 of 25 (36%) allocated to the saline group completed pain diaries. Those receiving saline had a higher mean pain burden of 629 ± 172 mm (mean ± standard deviation) than those receiving amethocaine (404 ± 75 mm); this could not be statistically tested because only a small number of diaries were returned.Corneal abrasions, foreign bodies, and welding flash burns can cause severe pain that may not be controlled by oral analgesia for up to 48 h. The outp9We performed a randomized, double-blinded, saline -controlled comparison trial to determine whether using amethocaine 0.4% eye drops hourly as needed for up to 48 h following uncomplicated corneal injury is a safe and effective method of analgesia as compared with topical saline. Persisting corneal defect was slightly more likely at 36–48 h in the amethocaine group than in the saline group, although the numbers were small (2/7 vs. 1/9). However, the secondary outcomes—oral analgesia used for eye pain, ongoing visual problems, need for unscheduled medical review, and patient satisfaction—did not differ between the two groups.Mean cumulative eye pain scores was lower for the amethocaine group. A high proportion (83%) of subjects could be followed up by telephone interview and the results suggest that amethocaine causes no clinically significant complications at 2 weeks. However, a formal ED eye assessment with quantification of the healing of the epithelial defect, rather than just information obtained through a telephone interview, would have been more reliable.Amethocaine was effective in reducing ocular pain compared with saline in this study; it conferred an analgesic benefit without causing any significant adverse sequelae at 2 weeks. This is the first published study evaluating the outpatient use of topical anesthesia following uncomplicated corneal injury, but there were several limitations in its conduct. The self-limiting nature of minor uncomplicated corneal injury reduces patient inclination to attend follow-up; in addition to leading to bias from loss to follow-up, this reduces the power of the study to detect any delay in corneal healing. Only patients with minor corneal injury expected to heal well within the 36–48 h follow-up period of the study were eligible for the study; the investigators did not attempt to impose the theoretical risk associated with a poorly sensate cornea on patients with corneal injury of higher severity that require a longer period to re-epithelize.The size of the corneal defect at recruitment and follow-up was not assessed as sophisticated ophthalmological assessment skills and the equipment required are usually not available in an ED. This situation would be expected at most non–eye hospital EDs and the simple practical slit-lamp assessment used in the study should render its findings more generalizable. However, this also meant that standardized evaluation of the rate of corneal healing was not possible, reducing the validity of comparison of corneal defect size between, and within the same, enrolled subjects due to interobserver and inter-event variability.There was no difference between the majority of amethocaine- and saline-treated subjects who could be contacted at 2 weeks  with respect to clinically or functionally significant adverse sequelae. However, it remains inconclusive whether dispensing topical anesthetics to patients discharged from the ED, who are otherwise unable to control pain following uncomplicated corneal injury, could potentially delay corneal re-epithelization, as only 34% (16 of 47) of the randomized subjects returned for follow-up at 36–48 h. This drop-out rate was unavoidable; on being contacted after failure to attend follow-up, most subjects cited insignificant pain or no pain and absence of visual problems as the main reasons for noncompliance.Although topical anesthesia has been found to be both safe and effective in the treatment of post-keratectomy pain,17 there As there was a statistically nonsignificant trend for persistence of corneal defect in the amethocaine group compared with the saline group (2/7 vs. 1/9), amethocaine needs to be used with caution in minor corneal injury. The increased risk of secondary corneal injury due to a poorly sensate cornea is compounded by poor compliance with attendance at review; there is also the possibility that the amethocaine drops will be stored for future unsupervised use. Although the majority of subjects in this study had no adverse sequelae at the 2-week telephone interview, two-thirds did not return for corneal assessment at 36–48 h.Loss to 36–48 h follow-up for a self-limiting condition such as uncomplicated corneal injury will remain a problem in any future study; higher numbers of subjects enrolled will only partly compensate for the suboptimal adherence to follow-up and the inherent bias resulting from the latter. There is a need for an adequately powered trial, with less follow-up attrition, to conclusively confirm or refute the common belief that topCompared with saline drops, amethocaine eye drops are probably not definitely safe but they are effective for topical analgesia in minor corneal injury. Until further definitive study, topical non-steroidal agents or long-lasting artificial tears may be preferred for the topical analgesia of minor corneal injury. Return for corneal re-evaluation will necessarily remain suboptimal in this self-limiting condition, leading to a bias even if study recruitment is good. Researchers conducting future studies may have to consider offering incentives such as reimbursement for expenses incurred in complying with follow-up or other strategies to reduce loss to follow-up.This small study suggests that at 2 weeks, there are no significant functional or clinical adverse sequelae in patients with minor corneal injury who were allocated topical 0.4% amethocaine. Such indirect evidence of safety would justify replicating this study, with improved recruitment and compliance for follow-up review. Treatment-related delay in corneal healing could then be more reliably assessed.We have conducted the first published randomized controlled trial to assess whether topical 0.4% amethocaine self-administered to a maximum recommended frequency of once every hour for 36–48 h is safe compared with topical saline in the management of patients with uncomplicated corneal injury who are discharged after assessment in the ED. However, it remains uncertain whether a brief period of patient self-administered topical anesthesia is safe to use for alleviating the acute pain resulting from corneal injury. Although no adverse effects were encountered at 2 weeks, amethocaine eye drops are not definitely safe in terms of healing of the corneal defect at 36–48 h, but they are effective for topical analgesia in minor corneal injury. Until further definitive study, topical non-steroidal agents or long-lasting artificial tears may be preferred for the topical analgesia of minor corneal injury. Return for corneal re-evaluation will necessarily remain suboptimal in this self-limiting condition, potentially leading to a bias even if study recruitment is good.


Postoperative pain control has been studied extensively, including many perioperative pain control procedures. Unfortunately, the impact of the surgical technique was not objectively studied.The aim of this study is to evaluate if the type of surgical dissection needed for extensive abdominal wall dissection actually has an effect in the reduction of postoperative pain or not.Forty adult patients, 19 males and 21 females, were randomly divided into two groups with each group containing 20 patients having different varieties of anterior abdominal wall ventral hernia. Patients in group I had their hernias and abdominal wall flaps dissected by only sharp dissection using scalpel. Patients in group II had their hernias and abdominal wall flaps dissected using mainly blunt dissection assisted by sharp dissection where blunt dissection could not do the job. All the patients had general anesthesia. No preemptive analgesia was used. Nalbufen was used as the only postoperative pain killer and the total amount used of it was treated as the indicator for the intensity of postoperative pain.The results of the present study showed that the total amount of Nalbufen used for the control of postoperative pain is significantly less in group I throughout the postoperative follow-up period.This study concludes that use of sharp dissection in cases of extensive abdominal wall dissection is statistically better than other methods of dissection in terms of postoperative pain control. Pain is an unpleasant sensory and emotional experience associated with acute or potential tissue damage. UnrelievAnesthesiologists had studied the role of different types of anesthesia and various types of anesthetics in the reduction of postoperative pain. Recently, pre-emptive analgesia has gained popularity and its role in the control of postoperative pain has been extensively studied. AlthoughThis work is a trial to study the relationship between different types of commonly used surgical dissection and the amount of postoperative analgesics needed to control postoperative pain – as an indication of the severity of postoperative pain – in patients with ventral hernias which actually need extensive abdominal wall dissection.®), and reinforcement with on lay nonabsorbable mesh repair (Proline or Ethicon). Patients in group I had their hernia and abdominal wall flaps dissected using only sharp dissection using scalpel. Patients in group II had their hernia and abdominal wall flaps dissected using mainly blunt dissection assisted by sharp dissection where blunt dissection could not do the job. All the patients had strict hemostasis using coagulation diathermy. Complete medical history and physical examination were done for all patients including assessment of vital signs and airway assessment. Investigations included CBC, PT, PTT, random and fasting blood sugar, serum creatinine and ECG. Patients were ASA I or II. All patients had general anesthesia. standard monitors including ECG, HR, NIBP, TEMP and ETCO2. Thiopental (3-5 mg/kg)was used for induction. Atracurium. 5 mg/kg for tracheal intubation. then halothane for maintenance of general anesthesia, intraoperative analgesia by diclofenac sodium 1 mg/kg IM, no preemptive analgesia was used but all patients received 5 mg. Nalbuphine given after complete recovery and just before leaving the recovery room to the inpatient ward. No preemptive analgesia was used but all the patients received 5 mg Nalbufen which was given after complete recovery and just before leaving the recovery room to the inpatient ward. Twenty milligrams of Nalbufen was diluted in 10 ml 0.9 saline solution (2 mg/ml) for every patient and he/she was given 2 ml (4 mg) on patient request, with a maximum dose of 20 mg every 24 hours. If any patient still needed analgesia after this 20 mg of Nalbufen, he/she were given diclofenac sodium. The total amount of Nalbufen needed was calculated for every patient in 3, 6, 12, 24, 36, and 48 hours from the time of giving the postoperative dose of Nalbufen. The statistical analysis was done using the SAS software, including actual means (±SE), coefficient of variability (CV%), and least square analysis of variance test.This was a prospective randomized controlled trial done in the Department of Surgery, Suez Canal University Hospital, Ismailia, Egypt. Forty adult patients, 19 males and 21 females, were randomly divided into two groups. Each group had 20 patients with different varieties of anterior abdominal wall ventral hernia. All the patients had their hernia repaired with anatomical facial repair, using monofilament nonabsorbable no. 1 suture material  and 8 males and 12 females in group II (blunt dissection). The ages of the patients ranged between 35 and 55 years. The two groups were nearly matched, with all ventral hernias needing extensive abdominal wall flap dissection and all the patients used nonabsorbable Proline mesh, either 15×15 cm or 30×30 cm. The total dose of Nalbufen needed for control of postoperative pain on patient request was used as an indicator for the severity of pain in 3, 6, 12, 24, 36 and 48 hours in each group collectively.The minimum, maximum and actual means (±SE) of total amount of Nalbufen used in every group are represented in Tables Except for the first 3 hours of follow-up in group I, most values of CV% in both the groups throughout the postoperative follow-up period were around 25% , and neaThe analysis of variance test  implies It had been once said that the single most important factor in preventing infection is the gentleness of surgical technique, i.e., the minimization of tissue injury. However, sophisticated methods directed at reducing contamination, if the operative technique is poor, can lead to higher infection rate. The sameThe present study was based on a clinical observation that patients who had their hernias done with sharp dissection did not ask for pain killers, as expected. Sex of the patients did not affect the amount of Nalbufen used for analgesia in both the groups. This actually ameliorates the sex effect on the results of this study as a source of bias. In the same time, the patients who had their flaps dissected by sharp dissection had used much lower amounts of Nalbufen for pain relief postoperatively than the patients who had their flaps dissected mainly by blunt dissection. The difference between the two groups was highly statistically significant. After exhaustive medical search throughout the internet, unfortunately, no papers were found reporting objectively the effect of surgical dissection on the level of postoperative pain in general surgery.During sharp scalpel dissection, the nerves in between the abdominal wall flap and the muscles of the abdominal wall are sharply and cleanly cut, whereas while performing blunt dissection, most of the nerves are avulsed during surgery, especially the small nerve endings away from the main perforators, which should be identified and coagulated before cutting. Sharp nerve cut results in tidy axonal transaction. In the contrary, blunt dissection results in avulsion of the nerve axons; this may lead to more edema and bruises of the nerve sheaths, causing more pain sensation and more neuroma formation later on. Also, pain mediators are produced in lesser quantities with sharp dissection than with blunt dissection; this may reduce pain sensation even with operations involving large extent of dissection as in ventral hernias. Also, blunt dissection usually results in more tissue edema, more interstitial hematomas, and more inflammatory response; all these factors may lead to more pain sensation and increase the amount of pain killers needed for analgesia postoperatively.This study concludes that sharp dissection is better than blunt dissection in the repair of ventral abdominal wall hernias, in terms of postoperative pain severity reflected by the amount of postoperative pain killers needed for postoperative analgesia.


Pain in critically ill patients in the intensive care unit (ICU) is common. However, pain assessment in critically ill patients often is complicated because these patients are unable to communicate effectively. Therefore, we designed a study (a) to determine the inter-rater reliability of the Numerical Rating Scale (NRS) and the Behavioral Pain Scale (BPS), (b) to compare pain scores of different observers and the patient, and (c) to compare NRS, BPS, and the Visual Analog Scale (VAS) for measuring pain in patients in the ICU.n = 113).We performed a prospective observational study in 113 non-paralyzed critically ill patients. The attending nurses, two researchers, and the patient (when possible) obtained 371 independent observation series of NRS, BPS, and VAS. Data analyses were performed on the sample size of patients . In ventilated patients, a moderate positive correlation was found between the NRS and the BPS . However, whereas 6% of the observations were NRS of greater than or equal to 4, BPS scores were all very low .Inter-rater reliability of the NRS and BPS proved to be adequate . The level of agreement within one scale point between NRS rated by the patient and NRS scored by attending nurses was 73%. However, high patient scores (NRS ≥4) were underestimated by nurses (patients 33% versus nurses 18%). In responsive patients, a high correlation between NRS and VAS was found  rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. In ventilated patients, the BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli. Pain is a frequently experienced problem in critically ill patients in the intensive care unit (ICU) . Pain maTherefore, pain assessment in the ICU remains a challenge for clinicians and researchers. There is no specific neurobiological parameter for the evaluation of pain, nor does an objective quantification of pain intensity or relief exist . VariousA prospective observational study was performed in a 30-bed surgical/medical ICU in a teaching hospital in Nieuwegein, The Netherlands. The medical ethical committee of St. Antonius Hospital approved the study protocol and waived the need for informed consent because the observational study design and pain measurement are part of the standard care.All patients in the ICU who were at least 18 years old were included between 27 June and 4 August 2005. Patients who received neuromuscular blocking medications or muscle-paralyzing drugs continuously, who were unconscious after resuscitation, who were quadriplegic, who suffered from a critical illness (poly)neuropathy, or who had an epidural catheter were excluded. Paralysis, whether caused by a pre-existing condition or by medication, makes the BPS unreliable.To assess pain intensity, three pain scales  were used. The BPS is used after an observation of the patient for about 1 minute and was validated in critically ill, sedated, and mechanically ventilated patients ,11. The The Ramsay Scale (RS) was used to assess the sedation level . The RS All patients received pain medication according to the local standard protocol, consisting of 1 gram of acetaminophen rectally three times daily and 10 mg of morphine subcutaneously four times daily or 30 to 50 mg of morphine per day using a continuous intravenous infusion, if required.Before this study, levels of pain were not systematically scored and recorded. During this study, assessments took place in all patients in the ICU twice a day (at 8.30 a.m. and 3 p.m.) during 1 month. Assessments were initiated by two researchers who were trainees in pharmacy and who had been working for 6 months under close supervision of two anesthesiologists of the Department of Anaesthesiology/Intensive Care and one ICU nurse. These researchers were not involved in the patient's care but took notice of the clinical and medical situation of the patient, similar to a physician on ward rounds. All assessments were made during non-nociceptive procedures in order to obtain basal pain scores. First, the researchers observed every patient for about 1 minute. Assessments of the researchers were made simultaneously but were independent of each other. Then, the researchers scored the BPS, NRS, and RS in order to prevent the outcome from being influenced by the patient's or nurse's score. The BPS was scored only in patients who were ventilated. Then, the attending nurse was asked to score the pain of the patient with the NRS. If the patient was responsive, the patient was asked to score the pain using the NRS and VAS. Gender, height, weight, year of birth, ICU indication, and relevant history were collected. Patients were classified in one of the two ICU indications, 'cardiothoracic surgery' or 'non-cardiothoracic surgery, with a skewed distribution for 'cardiothoracic surgery'. In this study, the 'NRS researcher' and 'BPS researcher' are defined by NRS rating and BPS rating by the researcher. The 'RS researcher' is defined by the RS rating by the researcher. 'NRS nurse' is defined by the NRS rating by the nurse. 'NRS patient' and 'VAS patient' are defined by the NRS rating and VAS ratings by the patient Table .For adequate use of the BPS, NRS, VAS, and RS, the two researchers attended a 4-hour training session (conducted by a trained ICU nurse), during which the BPS and RS were explained with examples of patients who were in the ICU at the time of the training. When the inter-rater reliability was acceptable according to a quadratic weighted Cohen's kappa of greater than 0.6, the researchers were allowed to score patients for the study .® version 6.2 . To correct for the different numbers of measurements per patient, one observation per patient was randomly selected. All statistical analyses were performed using this independent sample, while all measurements were plotted in the figures for better illustration. Kappa coefficients with quadratic weights were used to reflect agreement for ordinal scales  between the independent researchers. Weighted kappa penalizes disagreement in terms of their seriousness [s) were used to measure the degree of correlation for two ordinal variables. The null hypothesis that the correlation coefficient is zero was tested. A P value of less than 0.05 was considered statistically significant.Data were analyzed with the statistical software S-Plusiousness . Theoretiousness . The 95%A total of 138 intensive care patients entered the study, with a median of two observation series per patient (range 1 to 15). In total, 25 patients were excluded (15 patients because of incomplete collection of the data and 10 patients because of exclusion criteria), resulting in a total of 113 included patients. Table n = 83) and 'non-cardiothoracic surgery' (n = 30) in exact agreement (60% versus 57%) and agreement within one scale point (94% versus 93%).Table n = 75), the level of agreement within one scale point between NRS patient and NRS nurse was 73% compared with 58% for the NRS researcher, corrected for multiple observations per patient. Similar results were found for the exact agreement . The correlations between NRS of patient and nurses . Whereas 33% of the patients scored NRS values of greater than or equal to 4, only 18% of the attending nurses scored NRS values in that range. Apparently, particularly when the patient rated his or her pain as unacceptable, nurses tended to underestimate the pain level of the patient on the NRS.For the patients who were able to report their own pain levels .In responsive patients, there was a strong positive correlation between the NRS patient and the VAS patient  were NRS of 0 (no pain), whereas on the BPS, 68% of the observations were BPS of 3 (no pain). Besides, using the NRS, 6% of the observations were NRS of greater than or equal to 4, considered to be unacceptable pain. However, corresponding BPS scores were all low  and below the acceptable BPS of 5, which means that no unacceptable pain was observed using the BPS. There was no difference in the correlation between cardiothoracic patients and non-cardiothoracic patients  or between pressure-supported ventilated patients compared with volume-controlled ventilated patients .While a moderate positive correlation was found between the NRS nurse and the BPS researcher in ventilated patients . The correlation was weak in both cardiothoracic patients and non-cardiothoracic patients .The correlation between the NRS researcher and the RS researcher was low  were underestimated by both the nurses and the researchers as 33% of the NRS patient values were equal to or greater than 4 compared with 18% for the nurses. As it is known that the patients may underestimate pain by themselves , the were undn = 151 observations of 57 patients) were NRS of 0 (no pain), whereas on the BPS, a remarkable 68% of the observations were BPS of 3 (no pain). In addition, although 6% of our observations were NRS of greater than or equal to 4 , the BPrding to , a high The high non-response on the BPS can be explained by the short time of observation. During 1 minute of observation, the patient may seem pain-free (BPS of 3). However, using the NRS, a higher score may be rated as the nurse tends to include more background information of the patient . So the BPS reflects the objective visible behavior at one specific time point, whereas the NRS represents a global impression of pain, including several contextual factors during a longer time period. It seems, therefore, that the BPS should be used only in conjunction with the NRS nurse to measure pain levels the ICU.s = 0.84, P < 0.001, n = 75), suggesting that the VAS is also an adequate tool for measuring pain in about two thirds of the patients in our ICU. However, the VAS could be used in only 75 of 113 patients, in particular in patients with intact comprehension and abstraction, when recovering from critical illness, and just before leaving the ICU following cardiac surgery. Therefore, it is unknown whether this finding can be extrapolated to other ICUs.Various studies concluded that, compared with the NRS, the VAS is not an adequate tool in patients with decreased consciousness ,26. Thiss = 0.28, P = 0.078, n = 40). So the degree of pain intensity does not seem to depend on the level of sedation. This is important because these two scores should be able to distinguish between the level of analgesia and the level of sedation. Whereas high RS levels (deep sedation) may be expected in more severely ill patients experiencing more pain, patients with low RS levels (light sedation), in contrast, have more ability to show painful behaviors, resulting in the absence of a significant correlation.The correlation between the NRS score and RS score was low .Furthermore, the patients included in this study are characterized by a high percentage (73%) of post-cardiothoracic surgery patients and a 50% rate of mechanical ventilation, which was partly due to pain measurements before leaving the ICU, so extrapolation of the results to other ICUs may be limited. In addition, in our ICU, sedation levels are aimed at cooperative levels comparable to those of Kress and colleagues  (2000) aThe different scales show a high reliability, but observer-based evaluation often underestimates the pain, particularly in the case of high NRS values (≥4) rated by the patient. Therefore, whenever this is possible, ICU patients should rate their pain. In unresponsive patients, primarily the attending nurse involved in daily care should score the patient's pain. The BPS should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.• Especially unacceptably high patients' scores  are underestimated by nurses.• Whenever possible, intensive care unit patients should rate their pain, which is the 'gold standard' in pain measurement.• The Behavioral Pain Scale should be used only in conjunction with the NRS nurse to measure pain levels in the absence of painful stimuli.s = Spearman non-parametric rank correlation coefficient; RS = Ramsay Scale; VAS = Visual Analog Scale.BPS = Behavioral Pain Scale; ICU = intensive care unit; NRS = Numerical Rating Scale; rThe authors declare that they have no competing interests.SA carried out the practical work and drafted the manuscript. LG participated in the practical work and coordination, in revising the manuscript, and in the design and coordination of the study. AV participated in training the researchers for measuring pain. AB and DT participated in revising the manuscript critically. PB and HD participated in revising the manuscript critically and in the design and coordination of the study. SB carried out the statistical analysis. CK conceived of the study, participated in its design and coordination, and helped to draft the manuscript. All authors read and approved the final manuscript.


Older patients are typically underrepresented in clinical trials of medications for chronic pain. A post hoc analysis of multiple clinical studies of pregabalin in patients with painful diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN) was conducted to evaluate the efficacy and safety of pregabalin in older patients.Data from 11 double-blind, randomized, placebo-controlled clinical studies of pregabalin in patients with DPN or PHN were pooled. Efficacy outcomes included change in Daily Pain Rating Scale score, ≥30% and ≥50% responders, and endpoint pain score ≤3. Safety was based on adverse events (AEs). Primary efficacy was analyzed by analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction.2516 patients  were included in the analysis. Patients were grouped by age: 18 to 64 years (n = 1236), 65 to 74 years (n = 766), and ≥75 years (n = 514). Baseline mean pain and sleep interference scores were comparable across treatment and age groups. Significant improvements in endpoint mean pain were observed for all pregabalin dosages versus placebo in all age groups (p ≤ 0.0009), except for the lowest dosage (150 mg/day) in the youngest age group. Clinically meaningful pain relief, defined as ≥30% and ≥50% pain response, was observed in all age groups. The most common AEs were dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections. The relative risks for these AEs increased with pregabalin dose, but did not appear related to older age or type of neuropathic pain.Pregabalin (150-600 mg/day) significantly reduced pain in older patients (age ≥65 years) with neuropathic pain and improvements in pain were comparable to those observed in younger patients. Titration of pregabalin to the lowest effective dose should allow for effective pain relief while minimizing AEs in older patients with neuropathic pain. Given the common use of polypharmacy in older patients, the absence of known drug-drug interactions makes pregabalin an important treatment option for older patients with pain of neuropathic origin. Chronic neuropathic pain conditions, such as painful diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN), can be challenging to manage in older patients. Older patients tend to have multiple medical conditions and take several medications, which complicate treatment decisions. Concerns include the potential for drug-drug and drug-disease interactions and age-related changes in drug absorption, metabolism, and excretion -4. Sever2δ ligand with analgesic, anxiolytic, and anticonvulsant properties that is minimally metabolized with renal excretion, displays linear gastrointestinal absorption leading to a predictable dose-response relationship, and has no known drug-drug interactions [Pregabalin is a calcium channel αractions . Clinicaractions -17. In tractions ,12,13,15ractions ,14,15,17ractions . Pregabaractions . One sturactions .Clinical studies of therapies for chronic pain typically lack sufficient numbers of older patients to evaluate the safety and efficacy of analgesics in this population. Current evidence suggests that selection of treatment for neuropathic pain in older patients should be similar to that for younger patients, with the exception of slower, more cautious dosing and consideration for issues unique to the older population . The objThe goal of this analysis was to break down efficacy and safety data by specific age cut-offs, which would have been difficult or impossible to obtain using summary statistics from published reports. Furthermore, it has been suggested that study-level analyses can lead to biased assessments, and use of aggregated summary values has some limitations for explaining the heterogeneity of results -20. AcceData from 11 double-blind, randomized, placebo-controlled, Pfizer Inc.-sponsored studies that evaluated the efficacy and safety of pregabalin in patients with DPN or PHN were used for this analysis. Results from 9 of these studies have been reported . ResultsAll studies were conducted in compliance with the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice Guideline. The final study protocols, any amendments, and informed consent documentation were approved by the Institutional Review Board(s) and/or Independent Ethics Committee(s) at each investigational center. The clinical protocols were conducted in accordance with Food and Drug Administration Regulations.cr; defined as ≤30 mL/min [cr >60 mL/min received pregabalin 600 mg/day and those with CLcr values of >30 to 60 mL/min were assigned to 300 mg/day. Patients with DPN were required to have hemoglobin A1c levels ≤11%. Six of the 11 studies excluded patients who had previously failed to respond to gabapentin at dosages ≥1200 mg/day for the treatment of DPN or PHN [Eligible patients were male and female patients aged ≥18 years with DPN or PHN; one study required patients at sites in Austria to be ≥19 years of age. Patients with DPN had a diagnosis of diabetes mellitus type 1 or type 2 and a diagnosis of painful DPN for ≥1 years, except for 2 studies that included patients with painful DPN for ≥3 months  and ≥6 m0 mL/min ,16 or ≤60 mL/min ,12,14,170 mL/min , the dosN or PHN ,22,23.The primary efficacy measure was the endpoint average pain score on DPRS (0 = no pain to 10 = worst possible pain). Endpoint mean pain was based on patients' pain score ratings over the last 7 days of treatment. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group recommends the use of responder analyses rather than mean changes in pain to determine clinically meaningful change in pain in clinical trials of chronic pain . PatientFor the pooled analysis, patients with DPN or PHN were combined and stratified into the following age groups: 18 to 64 years, 65 to 74 years, and ≥75 years. Only data for pregabalin at dosages of 150 to 600 mg/day were evaluated because 75 mg/day is not an approved dosage. Demographics and baseline characteristics (mean DPRS and DSIS sleep interference scores) were summarized descriptively by treatment and disease groups.To explore the differential effects on pain among age groups, a treatment-by-age interaction analysis was performed on patients using analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction. Last observation carried forward (LOCF) was used to impute missing values for the evaluation of response rates for endpoint pain score ≤3 and 30% and 50% pain relief. The more conservative baseline observation carried forward (BOCF) method of imputation was also used to evaluate response rates for both 30% and 50% pain relief, but not endpoint pain score ≤3 since patients were required to have a pain score ≥4 on the DPRS at baseline for inclusion in these studies. The most common AEs (≥10% of any age or treatment group) were tabulated by treatment and age groups. The 95% confidence intervals (CI) for relative risks for pregabalin 300 mg/day (most common dosage) versus placebo were displayed by age groups.In total, 2516 patients were included in the pooled analysis: 1513 patients with DPN and 1003 patients with PHN. In the overall pooled group, 93.2% were white, 53.5% were male, and 50.9% were ≥65 years of age. Among patients with DPN, 57.6% were male and 32.6% were ≥65 years of age; among patients with PHN, 47.5% were male and 78.4% were ≥65 years of age , indicating a trend for decreasing placebo response with older age. Placebo patients aged 18 to 64 years showed the largest improvement in average pain score (-1.47) compared with either placebo patients aged 65 to 74 years  or aged ≥75 years . No significant differences in placebo pain response were observed between those aged 65 to 74 years and those aged ≥75 years (p = 0.3318).Significant dose-dependent reductions in endpoint mean pain score on DPRS were observed for pregabalin dosages of 150, 300, and 600 mg/day versus placebo for pooled age groups  at baseline. Because of these age-related impairments and varying criteria for dose reductions based on CLcr measurements, it cannot be assumed that patients in a particular dosage group had identical exposure to pregabalin, and this may have influenced the incidence of AEs in the higher dosage groups. Given that all 3 dosages of pregabalin were shown to significantly reduce pain in older patients with neuropathic pain, it is feasible to assume that some of the patients assigned to the higher dosage group may have achieved adequate pain relief with a lower dosage of pregabalin. Dizziness and somnolence are the most common AEs among older patients and potentially can be minimized by initiating pregabalin at low doses and slowly titrating to a dose at which the patient experiences pain relief, while taking into account any impairment in renal function. Titration of pregabalin to the lowest effective dose may be especially important for older patients with PHN.In all but one of the studies in this analysis, patients were assigned a dose of pregabalin (or placebo) based on the randomization schema of the study and not titrated based on response to pregabalin. Renal excretion is compromised in up to one-half of older patients , which pThe high placebo response in patients aged 18 to 64 years in the current pooled analysis may partially explain the lack of significant reduction in endpoint mean pain score for the pregabalin 150-mg/day dosage in this group. Interestingly, in the current analysis, a significant difference was found in placebo response on pain between younger (age <65 years) and older patients (age ≥65 years). A similar phenomenon has been observed in a pooled analysis of rizatriptan in patients with migraine . It is uThe choice of analgesic in patients with neuropathic pain of any age depends on the type of neuropathic pain, potential for AEs, comorbid conditions, and risk for drug-drug interactions. Comparison of the guidelines from the International Association for the Study of Pain Neuropathic Pain Special Interest Group, European Federation for Neurological Societies, and Canadian Pain Society found a consensus for the use of TCAs, gabapentin, and pregabalin as first-line treatments for neuropathic pain . Older pWhether the results from controlled clinical trials, which have strict patient enrollment criteria, are generalizable to patients encountered in clinical practice is always a concern. Pregabalin significantly reduced pain and sleep interference scores compared with pretreatment levels across a broad range of patients with refractory neuropathic pain in an open-label routine care setting . SeveralLimitations of this analysis include that it was a post hoc analysis. Unlike randomized clinical trials, the age and dosage groups were not balanced for the number of patients resulting in fewer patients evaluated in the older groups, especially at the highest pregabalin dosage. Analysis of data across multiple clinical trials with slightly different eligibility criteria and 2 different neuropathic pain conditions may have contributed to some of the variability in the results. Furthermore, large placebo responses in clinical trials of neuropathic pain may confound assessment of treatment differences. Because the study populations in this analysis were selected based on inclusion and exclusion criteria to express particular characteristics, the results may not be immediately generalizable to the patient population encountered in clinical practice.In this post hoc pooled analysis, pregabalin 150 to 600 mg/day reduced pain and improved sleep interference in older patients (age ≥65 years) with neuropathic pain. The improvements in pain in older patients were comparable to those observed in younger patients and clinically meaningful improvements in pain were observed in all age groups. The most common AEs were somnolence, weight gain, dry mouth, asthenia, dizziness, peripheral edema, and infection. The incidence of AEs did not appear to be related to older age or type of neuropathic pain, but did appear to be related to pregabalin dose. Slow titration of pregabalin to the lowest effective dose that provides pain relief should minimize the risk of AEs in older patients with neuropathic pain.cr: creatinine clearance; DPN: diabetic peripheral neuropathy; DPRS: Daily Pain Rating Scale; DSIS: Daily Sleep Interference Scale; PHN: postherpetic neuralgia; TCAs: tricyclic antidepressantsAEs: adverse events; AGS: American Geriatrics Society; CI: confidence interval; CLDavid Semel, T. Kevin Murphy, Gergana Zlateva, Raymond Cheung, and Birol Emir are full-time employees of Pfizer Inc.DS and GZ conceived the post hoc analysis and DS, GZ, TKM, RC, and BE participated in data analysis and interpretation. BE performed the statistical analyses. All authors participated in manuscript preparation and read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2296/11/85/prepubRelative risks for the most frequent adverse events for pregabalin 150 mg/day versus placebo by age group. The left panel shows the percentage of patients in each age group that reported a particular adverse event by treatment group. The right panel shows the relative risk of given adverse events in each age group for pregabalin versus placebo.Click here for fileRelative risks for the most frequent adverse events for pregabalin 600 mg/day versus placebo by age group. The left panel shows the percentage of patients in each age group that reported a particular adverse event by treatment group. The right panel shows the relative risk of given adverse events in each age group for pregabalin versus placebo.Click here for file


Chronic low back pain remains a major health problem in Australia and around the world. Unfortunately the majority of treatments for this condition produce small effects because not all patients respond to each treatment. It appears that only 25–50% of patients respond to exercise. The two most popular types of exercise for low back pain are graded activity and motor control exercises. At present however, there are no guidelines to help clinicians select the best treatment for a patient. As a result, time and money are wasted on treatments which ultimately fail to help the patient.This paper describes the protocol of a randomised clinical trial comparing the effects of motor control exercises with a graded activity program in the treatment of chronic non specific low back pain. Further analysis will identify clinical features that may predict a patient's response to each treatment. One hundred and seventy two participants will be randomly allocated to receive either a program of motor control exercises or graded activity. Measures of outcome will be obtained at 2, 6 and 12 months after randomisation. The primary outcomes are: pain (average pain intensity over the last week) and function  at 2 and 6 months. Potential treatment effect modifiers will be measured at baseline.This trial will not only evaluate which exercise approach is more effective in general for patients will chronic low back pain, but will also determine which exercise approach is best for an individual patient.ACTRN12607000432415 Low back pain is extremely costly causing great economic burden for Australia's health system, and considerable suffering for the individual . Around In Australia the most frequently used treatment for chronic low back pain is exercise . ExercisWhile some trials of exercise have reported large, durable and clinically important effects  others hTwo very different approaches to exercise are motor control exercise   That motor control exercise will be more effective in improving pain and disability at 2, 6 and 12 months.ii) The effect of graded activity (versus motor control) is greater in patients who are deconditioned and have negative beliefs about their pain.iii) The effect of motor control exercise (versus graded activity) is greater in patients with impaired control of movement and stability of the spine.A total of 172 subjects will be recruited from general practitioners, physiotherapy practices and public hospitals in Sydney and Brisbane. Contact has been made with these sites and consent letters have been obtained. Subjects will be screened to identify those who are unsuitable for exercise management of their low back pain because of significant co-morbidity such as serious spinal pathology or contraindication to exercise. To screen for serious pathology, the physiotherapist will conduct a diagnostic triage following the Royal College of General Practitioners' low back pain guidelines  and willinclusion criteria:Subjects will be included if they meet all of the following • Non-specific low back pain +/- leg pain persisting for at least 3 months duration• Currently seeking care for low back pain• Aged more than 18, less than 80 years• English speaker• Clinical assessment indicates that the subject is suitable for active exercises• Expects to continue residing in the Sydney or Brisbane region for study duration• Obtains a score of moderate or greater on question 7 or 8 of the SF-36.Question 7 – How much bodily pain have you had during the past week? None, very mild, mild, moderate, severe, very severe). [(tremely) .excluded if they have any of the following:Subjects will be • Known or suspected serious spinal pathology .• Nerve root compromise • Previous spinal surgery or scheduled for major surgery during the treatment follow-up period• Co-morbid health conditions that would prevent active participation in the exercise programs.Specific spinal pathology or contraindication to treatment may be suspected based upon the results of the screening questionnaire and the Physical Activity Readiness Questionnaire. If the assessor suspects the presence of any pathology or contraindication to treatment, these subjects should be further investigated by a registered physiotherapist and medical clearance obtained if necessary.Subjects receiving workers compensation will only be included in the trial if they have written consent from the nominated treating doctor, insurer and employer agreeing to their participation in the trial. The letters should state that they agree with the condition that only the trial treatments will be administered to the patient and acknowledges that the patient will be instructed not to seek other treatments during the trial treatment period.Participants will be allocated to treatment group using sealed opaque envelopes. Physiotherapists will allocate patients by drawing the next consecutive envelope allocated to their practice. A sticker containing the letter M (motor control) or G (graded activity) will be inside the envelope. After reading the sticker it will be attached to the patient's file. The therapist will not reveal the patient's allocation until the end of the study.Following the screening consultation, personal characteristics  and information about symptoms of low back pain will be collected. The following treatment outcomes will be measured at baseline, 2 months, 6 months and 12 months.1. Average pain intensity over the last week  ,232. Patient-generated measure of disability  ,233. Patient's global impression of change  ,234. Condition-specific measure of disability (Roland Morris Disability Questionnaire) 5. Generic measure of health status (SF-36 Version I) In addition subjects will be asked about their pain (average for preceding 24 hours and their average pain in the preceding week) once a month during one year. This data will be collected using a SMS (phone message) system. A SMS message will be sent monthly to all subjects reminding them to text the researcher with a number from 0–10 representing their average pain intensity over the preceding 24 hours and a number representing their average pain intensity over the preceding week. If subjects do not have a mobile phone they will be e-mailed monthly and asked to supply their average pain intensity score via return email. For patients that do not have a mobile phone or access to email, the average pain intensity will be recorded by phone. At the end of the study all participants will receive $10.00 to cover the cost of text messaging. A summary measure of the pain experienced over the 12-month period is provided by the area under the curve of the pain intensity/time curve. These measurements may better reflect the fluctuating nature of chronic pain than is possible with traditional outcome measures taken at a single time point. As the measures are novel the measurement properties are unclear and so we will regard this as a secondary outcome.To maximise attendance at follow-ups subjects will receive a reminder letter and a phone call 24 hrs prior to their appointment. Every attempt  will be made to obtain outcome data, regardless of subject's compliance with trial protocols. Follow-up measures will be scored by an investigator who is blinded to group allocation. At 2 months, information about side effects of treatment will be collected from all subjects using open-ended questioning. At each follow-up, information on use of other pain-related treatments will be recorded as will the patient's compliance with their home exercise program.Accordingly we will take measures that reflect poor motor control of the spine e.g. trunk proprioception, trunk stiffness, trunk muscle response, tests of deep muscle control. The rationale for graded activity is that people with chronic low back pain are generally deconditioned as a result of injury or disuse and that this deconditioning underpins their chronic symptoms. Additionally many people with chronic low back pain have beliefs about pain and injury that are unhelpful to recovery. With graded activity the physiotherapist teaches the patient how to increase their activity. Logically this treatment should work best in patients who are deconditioned and have unhelpful beliefs about their back pain. Patients with high levels of habitual activity are less likely to benefit. Accordingly we will take measures of aerobic fitness, habitual activity level, kinesiophobia and self-efficacy.The treatment rationale for the two types of exercise suggests potential treatment effect modifiers. The rationale for motor control exercise is that people with low back pain have poor control and coordination of the trunk muscles that results in control of movement and stability of the spine that is less than optimal ,26. ThisWe will collect baseline data about clinical/demographic data, measures of beliefs and attitudes about pain, measures of physical activity and fitness and measures of control and coordination of the lumbar spine and pelvis.LBP screening questionnaire PASS-20  Pain Self Efficacy Questionnaire International Physical Activity Questionnaire (IPAQ) Three minute step test As no in-vivo measures of "instability" have been validated assessment of instability is currently dependent on subjective data. A recent Delphi survey of international experts  has deveProprioception is a critical component of control and determines the effectiveness of control strategies. Although studies of repositioning have provided variable results ,35, receActive trunk stiffening by the trunk muscles can be evaluated in a dynamic task using an indirect measure of trunk stiffness and damping . The response of the trunk to removal of a load is modelled as a second order system and resolved for stiffness, damping and mass. People with low back pain have been shown to have increased stiffness and decreased damping The response of the trunk muscles to removal of a load from the trunk has been shown to predict occurrence and recurrence of pain . This meThis test is a novel measure of a subject's ability to activate the deep abdominal muscles. Until recently recruitment of the deep abdominal muscles could only be assessed with invasive EMG recording techniques that have limited application in large clinical trials. We have recently solved this problem by developing an ultrasound test  that proWe understand that the refined laboratory measures we propose may not all be viable in clinical practice. However it is important to use the best available measure to clearly establish the predictive ability of each factor. Equipped with this information we can then focus our attention on developing clinical versions of the tests that are shown to be important predictors.Subjects in each group will receive 12 one-hour treatments over an 8 week period, i.e. 2 sessions/week in the first month and 1 session/week in the second month and 2 additional 1 hour follow-up sessions at 4 & 10 months. Patients will be advised to do home exercises for at least half an hour per week in the first month and one hour per week in the second month. However, the type of exercises, intensity and amount done per day will be performed at the discretion of the physiotherapists. The treatment session and home exercises will add up to 20 hours of treatment. In both exercise programs an individualised program for each patient is prescribed. The treatment sessions are designed to become less frequent over time to encourage independence. Patients with continued pain following all sessions will be asked to continue their home exercise program until pain-free for a week. If a recurrence occurs, re-initiation of the home program will be advised. This is consistent with current clinical practice.graded activity program is based upon the treatment approach reported by Lindstrom [• The indstrom  and idenindstrom . At the Each subject will carry out a form of aerobic exercise , stretches, functional activities, activities to build speed, endurance and coordination and trunk and limb strengthening exercises. Subjects will be given an individualised home exercise program that will be regularly evaluated by the physiotherapist.motor control exercise program is based upon the treatment approach reported by Richardson et al [• The on et al , O'Sullion et al  and Moseon et al  and simion et al . The appon et al  and leadon et al ,44. In ton et al . Other tA treatment demarcation table was developed to help the trial clinicians to identify salient features from each of the interventions and to avoid unintended contamination between the two treatment approaches  to achieve pain recovery (pain ≤ 1 out of 10 (35)) and 95% confidence intervals.Individual variables will be tested for their association with treatment effect by adding a predictor × treatment group interaction term to the regression equation.interaction effect that is to be detected. We argue that small interaction effects are not clinically significant and we have planned the study with sufficient power to detect the following clinically important interaction effects.Brookes and colleague's  simulatiWe have taken the SD estimates from our previous trials ,13. WithThe trial includes key methodological features that have been recognised as minimising bias in clinical trials: true randomisation, concealed allocation, specification of eligibility criteria, blind outcome assessment, patient blinding, blind analysis and intention-to-treat analysis. The nature of the treatments precludes blinding of patient and treatment provider.We will use an exploratory approach and will test a wide range of potential predictors of treatment response. We acknowledge that any predictor identified in the analysis should be interpreted with caution until confirmed in subsequent independent studies.Our choice of outcomes is consistent with best practice recommendations for clinical trials studying chronic pain  and backWe have presented the rationale and design of a randomised controlled trial comparing the effect of motor control exercises and graded activity in a group of patients with chronic non specific low back pain with an analysis of treatment effect modifiers. The results of this trial will be published as soon as they are available.The authors declare that they have no competing interests.LGM, JL, CGM, PWH, MN, LT, JHM and RS were responsible for the design of the study. LGM and JHM will act as trial coordinators. All authors have read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


For maintenance of analgesia the patients of Group PCEA self administered 8 ml bolus with lockout interval of 20 minutes of above solution on demand with no basal infusion. While the patients of Group PCEA + CI received continuous epidural infusion at the rate of 10 ml.hr-1 along with self administered boluses of 3 ml with lockout interval of 10 minutes of similar epidural solution. Patients of both groups were given rescue boluses by the anaesthetists for distressing pain. Verbal analogue pain scores, incidence of distressing pain, need of supplementary/rescue boluses, dose of bupivacaine consumed, maternal satisfaction and neonatal Apgar scores were recorded. No significant difference was observed between mean VAS pain scores during labor, maternal satisfaction, mode of delivery or neonatal Apgar scores. But more patients (n=8) required rescue boluses in PCEA group for distressing pain. The total volume consumed of bupivacaine and opioid was slightly more in PCEA + CI group. In both the techniques the highest sensory level, degree of motor block were comparable & prolongation of labor was not seen. It was concluded that both the techniques provided equivalent labor analgesia, maternal satisfaction and neonatal Apgar scores. PCEA along with continuous infusion at the rate of 10 ml/ hr resulted in lesser incidence of distressing pain and need for rescue analgesic. Although this group consumed higher dose of bupivacaine, it did not affect maternal or neonatal safety.Patient controlled epidural analgesia (PCEA) is a well established technique for pain relief during labor. But the inclusion of continuous background infusion to PCEA is controversial. The aim of this study was to assess whether the use of continuous infusion along with PCEA was beneficial for laboring women with regards to quality of analgesia, maternal satisfaction and neonatal outcome in comparison to PCEA alone. Fifty five parturients received epidural bolus of 10ml solution containing 0.125% bupivacaine +2 µg.ml Safe foetal outcome without any adverse maternal effect is the chief goal of pain relief during labor and lumbar epidural analgesia is the most efficient and widely employed modality for this. After initiation of epidural analgesia by bolus dose, many techniques have evolved for subsequent maintenance of analgesia such as intermittent boluses by the clinicians, midwives or patient herself and continuous epidural infusion. The concept of patient controlled epidural analgesia (PCEA) was introduced during labor so that laboring women could control the dose of epidural medication according to their need due to change in labor and pain patterns1The purpose of this prospective randomized study was to investigate whether addition of continuous basal infusion to PCEA affected quality of labor analgesia maternal satisfaction, mode of delivery and neonatal outcome. We also investigated the need for anaesthesiologist administered additional rescue topups and the dose of bupivacaine consumed during labor & vaginal delivery.The study was conducted on 55 full term parturient women of ASA status I and II of mixed parity who were willing for epidural analgesia during labor. The women included in the study had singleton pregnancy with vertex presentation, had no contraindication to epidural analgesia and who were able to use PCA pump. The study was undertaken after Institutional Ethical Committee approval and informed written consent.2-4 interspace with 18 G Touhy's needle. Loss of resistance to air was used for localization of epidural space. The catheter was taped in place, leaving 3-4 cm in the space. The patients were randomly divided into two groups according to computer generated randomization.Before institution of the epidural block demo- graphic data, parity, gestational age condition of the membrane, cervical dilatation, vital parameters and FHR were noted and 500 ml of Ringer lactate was given intravenously. Epidural block was given after 3-4 cm cervical dilatation in sitting or lateral position by a third year anaesthesia resident in L−1 of fentanyl through the epidural catheter. The anaesthetist programmed the PCEA pump  to deliver 8 ml bolus of the above solution on demand with lockout interval of 20 minutes  or to deliver a continuous epidural infusion of above solution at the rate of 10 ml/hr with demand bolus of 3 ml of above solution with lockout interval of 10 minutes (Group PCEA + C I). In both the groups maximum upper limit of epidural solution was 25ml/ hour. The women were told to press the demand button whenever the analgesia was inadequate and to expect some relief within 5–6 minutes. The anaesthetist was called to give additional epidural injection if analgesia was unsatisfactory and pain was distressing. The number of times the anaesthetist gave rescue analgesic was recorded.All the patients received an initial bolus dose of a 10 ml solution containing 0.125% bupivacaine + 2 mcg.mlPain relief was assessed at 20 minutes and then hourly by an observer (who was unaware of the group) using Verbal Analog Scale of 0 – 10 where 0= no pain & 10= worst pain. Highest level of sensory block, degree of motor block , number of additional supplements by anaesthetist, total dose of bupivacaine consumed per hour & and during the labor, mode of delivery and neonatal Apgar scores were recorded. SpO2, heart rate and BP were monitored throughout the labor. FHR was monitored continuously using cardiotochograph. Any adverse effect such as weakness of limbs, hypotension, arterial desaturation and pruritus were noted and managed if required.2 test was used to compare analgesic quality and p<0.05 was considered as significant. We calculated that a sample size of minimum 25 patients per group would give the study a power of 80% to detect a statistically significant difference in the verbal analogue pain score.For statistical calculation the software SAS 9.13 was used. The data are presented as mean ± SD or % or number of patients. One way analysis of variance was used to evaluate differences in continuous variables across the groups followed by Bonferroni's test for multiple comparisons. XThere was no difference between the two groups regarding maternal demography and obstetrical characteristics. Duration of labor, incidence of caesarean delivery and Apgar scores were also comparable between the groups . Total vThe time for first demand bolus dose after initial bolus was significantly longer in PCEA + CI group than in PCEA group. . Analgesia was assessed hourly on a verbal analogue score (VAS). There was no significant difference in mean VAS pain scores in both the groups indicating similar analgesia. The scores were between 0-2 at majority of the assessment times. But more patients (8 vs 2) demanded rescue boluses by the anaesthetist due to distressing pain in PCEA only group (27%) compared to PCEA+CI group (8%) as shown in Both the groups provided equivalent labor analgesia and maternal satisfaction. The chances of caesarean delivery were also not increased in any group. No difference in the cephalad extent of sensory analgesia, motor block or neonatal Apgar score were observed. Although mean pain scores throughout the labor and delivery were similar in both groups, significantly more patients in PCEA group required supplementary boluses by the anaesthetist due to distressing pain particularly towards the end of first stage of labor. Many previous investigators reported occurrence of breakthrough pain requiring additional rescue analgesia by clinicians38−1 of fentanyl for maintenance of labor analgesia. They reported reduced incidence of breakthrough pain and maximum pain scores in patients receiving PCEA + basal infusion. Maternal satisfaction was also higher in these patients. Similar findings were reported in other studies379Ocampo et al (2006)−1 of sufentanil. The verbal pain scores, number of supplemental boluses and maternal satisfaction was comparable in all the four groups. The patients receiving 6 or 9 ml/hour of basal infusion consumed more ropivacaine but without any untoward effect such as dense motor block or higher sensory level or hypotension. They concluded that background in-fusion was unnecessary as it did not improve maternal comfort and satisfaction or obstetrical outcome despite use of more local anaesthetic and opioid but increased the cost of cares. Theonaz et a (2006)However some authors do not concur with these reports. Boselli et al 2004)4 randomlA potential drawback of PCEA technique is risk of patients receiving higher amount of local anaesthetic leading to high block568PCEA can theoretically adjust for individual pain threshold, allowing patients to use only the analgesic dose needed111389121415On the basis of our results we found that the technique of PCEA during labor was safe, effective and gave the women a feeling of ‘self control’ on pain. The addition of background infusion to PCEA resulted in more constant pain relief with lesser episodes of distressing pain demanding rescue boluses from anaesthetist. In fact it is difficult to convincingly prove which method is superior to other in a relatively small sample size. Before conclusion we say that each centre should select a technique which is suitable depending upon the availability of anaesthetist, equipment and expectation of parturient as well as obstetrician.


Our previous work showed higher tumour necrosis factor (TNF)-α levels in patients with chronic low back pain (cLBP) compared to healthy controls. However, patients with depression as a comorbidity did not have higher TNF-α levels in comparison to patients without depression. In this study we investigated the influence of depression on therapy outcomes such as TNF-α serum levels, pain intensity and back function in patients with cLBP. Our hypothesis was that patients with both cLBP and depression benefit no less than patients with cLBP alone from the multidisciplinary pain therapy.A total of 58 patients with cLBP alone or with both cLBP and depression were age- and sex-matched with 29 healthy controls. Serum concentrations of TNF-α were assayed at the beginning of the study (T0) and 10 days (T1), 21 days (T2), and 180 days (T3) later. The clinical outcomes such as pain intensity, as well as back function, sleep, exercise, alcohol and nicotine consumption were documented. In the first three weeks, all patients underwent multidisciplinary therapy based upon biological, psychological, physical and psychosocial components.P = 0.002 for cLBP+DE, P = 0.004 for cLBP) than healthy controls (HC) that normalized after 10 days of therapy and remained similar to healthy controls. During the follow-up, the depression scales were normalised and pain intensity was significantly reduced. Both evidences processed parallel to the reduction of TNF-α levels, which correlates neither with depression score nor with pain intensity at any time point.Over the whole course there were no differences in TNF-α level between cLBP patients with and without depression. At T0, both cLBP patients with (cLBP+DE) and without (cLBP) depression showed significantly higher TNF-α serum levels (Depression as a comorbidity to chronic low back pain did not influence the serum TNF-α level in the course of six months, but seemed to affect the success of therapy. cLBP patients with comorbidity of depression benefit from multidisciplinary pain therapy not only to the same extent but also to a greater degree than cLBP patients without depression. Patients with chronic pain have mostly additional psychiatric diseases. The range lists from the most to the fewest constellation include the affective diseases (depression), psychopharmaca associated diseases, somatoforme and anxiety disorders which are more frequent in chronic pain patients than in healthy subjects ,2. The CTo date, however, pain and depression have been considered as separate entities and therefore treated in isolation. The number of therapy resistant patients with chronic pain who could not be helped by the conventional therapy and, therefore, still looking for further medical help, is calculated at about 400.000 to 700.000 in Germany. The reasons for the breakdown of conventional therapy are isolated therapy of assumed causal causes or mostly only drug therapy or passive treatment strategies  without Over the past 10 years we have performed in our clinic a multidisciplinary pain therapy which was based on biological, psychological, physical and psychosocial components. This therapy comprised six-hour sessions on five days per week for three weeks, giving a total of 90 hours . The goaOur previous work showed great successes with the multidisciplinary pain therapy ,21, whicWe wonder whether the changes in TNF-α level could influence the development of depressive symptoms, if we follow up for six months the course of TNF-α level, depression scores parallel to pain intensity. The hypotheses of this prospective, longitudinal study were 1) patients with both cLBP and depression benefit to the same degree from the multidisciplinary pain therapy; 2) the changes of TNF-α level are associated with development of depressive symptoms.All participants gave informed consent, and the study was approved by the local ethics committee of the University of Heidelberg, Germany. Participants were consecutively recruited from the Department of Orthopaedic Surgery of the University of Heidelberg. Each group of 29 patients with chronic low back pain (cLBP) alone or cLBP together with depression (cLBP+DE) were matched with 29 healthy controls (HC) by age and sex. This prospective longitudinal study was conducted over a period of six months Table .The inclusion criterion for pain was cLBP as the main symptom, defined as disabling pain of at least six months' duration that led to the patient being on sick leave for at least six weeks. Patients with other pain locations as their main symptom and patients with multiple major pain locations were excluded from this study.The inclusion criteria for the diagnosis "depression" were: (i) an ICD-10 diagnosis of a current and an at least moderate depressive episode; (ii) a minimum CES-D score of 25.Exclusion criteria in patients and controls were: tumour disease (diagnosis from history and by radiographic/MRI examination); trauma/fracture (history and radiographic examination); inflammatory systemic disease or infection, for example, spondylodiscitis ; nucleus pulposus prolapse with corresponding radicular pain ; structural pathology of the lumbar spine, for example, spinal stenosis or spondylolisthesis ; rheumatological disease; serious cardiopulmonary, vascular or other internal medical conditions; any sensorimotor and/or neurological deficits in the lower extremity ; spinal surgery in the year before admission to multidisciplinary therapy; radiographically apparent degenerative changes in the lumbar spine , Day 10 (T1), Day 21 (T2) and finally at six months (T3) follow-up. Patients were additionally evaluated by standardized questionnaires and physical examinations at these time points.Average pain intensity of all patients was determined from a visual analogue scale recording from 0 (no pain) to 10 (severe pain) during the last 24 hours and last week.Measures of pain-related disability was assessed by using the Roland and Morris questionnaire , which ir = 0.49) and increases with recovery from depression (r = 0.86) [The CES-D is a well-established self-reporting instrument to assess the level of depression with 20 items and a potential overall score of 0 to 60. It has high specificity (94%) for the identification of acute depression if a score of at least 23 points is reached and the correlation coefficient to other instruments for measuring depression, such as the Hamilton Depression Scale, is acceptable ( = 0.86) .To identify other confounding factors, at each time point the patients filled in this standardized questionnaire about sleep duration, alcohol and nicotine consumption, exercise and SF-36 questionnaire.The SF-36 questionnaire was originally developed for the Rand Corporation's Health Insurance Experiment ,27. It iTo identify confounding factors of medication, drug intake in the two groups was studied accordingly to the ATC Classification System (ATC System).At the given time points, venous blood was taken from the cubital vein between 8 a.m. and 9 a.m. Blood samples were centrifuged at 2,000 rpm at 4°C within 30 minutes of withdrawal and serum was stored at -80°C. TNF-α serum levels were analysed in duplicate using a Bio-Plex cytokine assay  according to the manufacturer's instructions. Median fluorescence intensity (MFI) of standards and patient samples were determined. Using the Bio-Plex Manager software, serum levels of TNF-α were deduced from the standard curve. The intra-assay coefficient of variation was 5 to 10%.t-tests with Bonferroni correction and a P < 0.05 was used. ANOVA tests were used for analysis of repeated measures. Correlations between the individual groups and cytokines were investigated using the χ2 test, Fisher's exact test, and the phi coefficient. Drug intake was analysed as captured/non-captured without considering the dose. The nonparametric McNemar test was used to identify significant changes in medication during the six-month study period. Correlations of medication according to the ATC System with cytokine levels were calculated using the χ2 test, Fisher's exact test, and the phi coefficient. P-values below 0.05 were considered statistically significant; those below 0.01, highly significant. The data were analysed using SPSS 15.0 software .In case of significant results, single P = 0.002 for cLBP+DE, P = 0.004 for cLBP). At T1, T2 and T3, no differences in TNF-α serum level were found between patient group and the healthy controls (P = n.s.). No differences in TNF-α levels between the cLBP+DE group and the cLBP group were seen at any time . From T1 to T2, only the cLBP+DE group showed a significant increase (P = 0.004) in TNF-α levels; in the cLBP group, TNF-α levels were unchanged. From T2 to T3, TNF-α levels in both cLBP groups decreased significantly . At T3, TNF-α levels were significantly decreased in both cLBP groups compared to the level at T0   but not at T3. At T3 (six months after therapy) the CES-D scores of the two groups were similar . Between T2 and T3 there were no significant changes. Over the total study period of six months only the comorbid cLBP+DE group showed a significant decrease (P < 0.001) . The cLBP+DE group still showed this significant difference in both pain intensities after six months at T3 (P < 0.001), at which time they demonstrated a 49% (24 h) and 41% (7 d) amelioration of perceived pain compared to T0, while patients with only cLBP improved their perceived pain only 15% (24 h) and 11% (7 d) in the total study period (each n.s.) , but not at T2. Three weeks after initiation of the therapy both groups of patients displayed improvements in back function: 35% in cLBP+DE and 25% in cLBP. These changes were significant in both groups  (Table Patients with both cLBP and depression (cLBP+DE) showed worse back function than patients with cLBP alone at T0 (P = 0.037) and nicotine  in the previous 24 hours (Table There were no differences in reported sleep duration (in the past 24 hours) or alcohol and nicotine consumption (in the past 24 hours) between cLBP+DE and cLBP alone at the beginning of the study period, or between admission and discharge in cLBP+DE. However, at the end of the study a higher proportion of the formerly depressive cLBP patients reported consumption of alcohol  at T2 and of 25% at T3 (P = 0.01), while cLBP+DE patients improved the PCS for 8% at T2 (P > 0.05) and 17% at T3 (P = 0.036) respectively.The PCS scores of both patient groups did not differ at any time points. Compared to T0, cLBP patients displayed an amelioration of 13% (P < 0.001) and T2 (P < 0.001) but not at T3. Compared to T0, cLBP+DE patients improved the MCS for 25% at T2 (P < 0.001) and 57% at T3 (P = 0.002) respectively, while cLBP patients displayed an amelioration of 11% at T2 (P = 0.001) and of 4% at T3 (P > 0.05).The MCS scores was significantly higher in cLBP group than cLBP+DE at T0 (P = 0.037).There was no significant difference in medication (inclusive antidepressants) intake between the two groups at any time point, except that patients in the cLBP+DE group were taking significantly more NSAIDs (M01A) than patients with cLBP alone at T0 (P = 0.039) and of NSAIDs from 28% to 7%  were observed in the cLBP+DE group and of opioids  from 28% to 7% in the cLBP group.No significant differences were found between the two groups. Comparing T0 and T3, significant reductions in daily intake of analgesics from 28% to 3%  in the comorbid depression group (cLBP+DE), but not in the cLBP group without depression. A negative correlation between TNF-α serum level and intake of analgesics was found at T0 in cLBP+DE  and a positive correlation between TNF-α serum level and NSAIDs at T3 in cLBP . But all these significances disappeared after adjustment by Bonferroni-correction.No correlation was found between TNF-α serum level and age, sex, BMI, CES-D score or back function. The single correlation between TNF-α serum level and pain in the previous week was found at T3  or more factors together play a role in the normalization of TNF-α serum level so that the synergistic effect of all elements trigger the reduction of depressive and pain scores. The mechanisms can be explained as follows:In regard to exercise therapy, it is known that exercise modulates the inflammatory response through neuroendocrine mechanisms. All exercise-induced changes in the innate/inflammatory response are mediated by stress hormones, mainly gluococorticoids and catecholamines ,39. SincIn terms of psychotherapy, to date, randomized controlled trials have supported the efficacy of cognitive behavioural treatment (CBT) in treating both major depression  and painPotential confounding factors for TNF-α serum levels were analysed in this study. For many clinical parameters such as age, sex, BMI, sleep duration, exercise activity, pain intensity, physical composite scores were comparable between patients of both groups. Age, sex, BMI, CES-D score and back function did not correlate with TNF-α serum level. The single correlation between TNF-α serum level and pain during the previous week was found at T3 in the comorbid group but not in the cLBP group without depression. The fact that at the end of the study a higher proportion of the formerly depressive cLBP patients reported alcohol and nicotine consumption in the previous 24 hours  than patients with cLBP alone (7%) and used these drugs significantly less at T3 (7%) than at T0. NSAIDs are able to inhibit TNF-α production and TNF-α serum level at T0 was similarly high in both groups although NSAIDs intake in comorbid group was significantly greater at T0. So it is possible that the TNF-α serum level was higher in the comorbid group and reduced by NSAIDs intake at T0. But there is no correlation between NSAIDs and TNF-α in cLBP+DE group. In the course of the study TNF-α serum levels of boths groups were significantly lowered from T0 to T3 without a distinction to the level healthy controls at T3. In summary regarding TNF-α we suggest that multidisciplinary pain therapy may be responsible for the normalisation of its level without an impact of medication.One primary limitation of our study is the small sample size. Therefore, the results from this study should be further confirmed in a larger collective. However, our study addresses for the first time a timely topic regarding the shared biological underpinnings of pain and depression, and it employs longitudinal methodology. Our results indicate therapeutic options that target both pain and depressive disorders including cognitive behavioral therapy, exercise, and pharmacotherapy. Future research is needed to further clarify the multiple interactions of pain and depressive disorders, including effects on neurohormonal-cytokine interaction, which will aid in the development of more effective treatment strategies addressing all symptoms with which a patient might present.The findings of this study suggest that depression as a comorbidity to cLBP did not influence the serum TNF-α level during six months' follow-up, but did affect the success of therapy. cLBP patients with comorbid depression benefited more strongly from multidisciplinary pain therapy than cLBP patients without depression. We assume that one or more elements of the therapy  may improve subjective pain perception, mood and immune function . However, this needs to be confirmed in a further study involving a larger collective.th Revision; IL: interleukin; MCS: Mental Composite Scale; MDD: major depressive disorder; MDPT: multidisciplinary pain therapy; NSAIDs: non-steroidal anti-inflammatory drugs; PCS: Physical Composite Scale; SF-36: 36-item short form health survey; TNF-α: tumour necrosis factor alpha.ATC: Anatomical Therapeutic Chemical Classification; CBT: cognitive behavioural treatment; CES-D: German version of Centre for Epidemiological Studies Depression Scale; ICD-10: International Statistical Classification of Diseases and Related Health Problems: 10The authors declare that they have no competing interests.HW conceived the hypothesis for the manuscript, participated in data collection, wrote the first draft of the manuscript and had primary responsibility for the manuscript process. CA participated in data collection, performed the statistical analyses, contributed to and approved the final manuscript. WR participated in the interpretation of data, and contributed to and approved the final manuscript. MS conceived the study and participated in its design and helped to draft the manuscript. All authors read and approved the final manuscript.