Postoperative pain has negative consequences on patients’ outcomes after cardiac surgery. Routine management with opioid and or non-steroidal anti-inflammatory medications has several disadvantages. Dexmedetomidine is a selective α2 agonist used for sedation and analgesia. The use of dexmedetomidine for postoperative pain management and decreasing delirium and agitation in cardiac surgery patients is a matter of debate. Our objective was to determine the role of an early administration of dexmedetomidine in decreasing opioid use post-cardiac surgery and its effects on the quality of postoperative recovery.Medical records of 120 patients admitted to the cardiac surgery intensive care unit (CSICU) after coronary artery bypass grafting (CABG) in two cardiac centers between December 2015 and December 2016 were reviewed. Patients were divided into two groups. Group A included 55 patients who received dexmedetomidine in a dose of 0.2–0.4 mcg/kg/h on admission to CSICU, and group B included 65 patients who did not receive dexmedetomidine. The primary outcome was the pain score immediately after extubation, and the secondary outcomes included post-extubation sedation and pain scores for 12 h.p < 0.001), significant decrease in cumulative morphine received , favorable reduction in heart rate in dexmedetomidine group (80 ± 1.9 b/min) compared to 96 ± 8.8 b/min in the other group (p = 0.017), and smoother recovery from general anesthesia.There were significant decrease of the pain scores in dexmedetomidine group that continues through the 3rd, 6th, 8th, and 12th hour readings after surgery with mean modified Ramsay scores 0.1 ± 0.0, 0.89 ± 2.05, 0.35 ± 0.1, and 0.12 ± 1.1 respectively compared to 0.46 ± 1.15, 3.46 ± 2.93, 0.98 ± 1.90, and 0.12 ± 1.1 in group B (Administration of dexmedetomidine in the early postoperative period can be safe. It may reduce the use of opioids, has sedative, analgesic, and sympatholytic effects that could play a useful role during the management of coronary artery bypass patients, and may improve postoperative recovery. Postoperative pain after cardiac surgery has a negative impact on the outcome, in addition to the patients’ experience. Tachycardia, hypertension, arrhythmias, and myocardial ischemia are frequent postoperative findings. Most postoperative pain management protocols are opioid-based, which have a dose-dependent analgesic effect .On the other hand, opioids have a number of undesired side effects, including nausea, vomiting, decreased gastrointestinal motility, respiratory depression, drowsiness, and hemodynamic effect with large doses . MoreoveDexmedetomidine (DEX) is a highly selective α2 receptor agonist that provides better sedation, analgesic, and anxiolytic effect. This property is considered unique among sedatives used for intensive care units generally , 5. ManyMoreover, recent findings show that such patients have a lower incidence of delirium over comparators , 9. On tData of all patients admitted to the cardiac surgery intensive care unit (CSICU) following CABG, between December 2015 and 2016, were retrieved from the medical records after approval from the local medical ethics committee. Patients’ confidentiality was maintained by removing any identifying information from the data set before further usage and analysis. The variables and their values were coded into an alphanumeric format for concealment with few designated persons having the coding key.A hundred and twenty patients were included in the study. Patients with renal failure, prolonged postoperative intubation for more than 8 h because of hemodynamic instability or bleeding, and patients who had re-exploration were excluded.Patients were divided into two groups: group A included 54 patients who received postoperative DEX infusion for sedation, and group B included 66 patients who did not receive DEX.All patients were intubated, ventilated, and sedated by propofol intravenous (IV) infusion 25–50 μg/kg/min. On admission to CSICU, vital signs were recorded, and group A patients were started on DEX IV infusion 0.2–0.4 μg/kg/h. while patients in group B were maintained only on propofol infusion.Vital signs, including heart rate (HR), oxygen saturation, and end-tidal carbon dioxide, were continuously monitored, and blood pressure was monitored both invasively and non-invasively. Patients were started on acetaminophen 1 g IV every 6 h, and 2–3 mg of morphine were administered intravenously if the pain was suspected in case of unexplained tachycardia and hypertension when the patients were still intubated.We reviewed the difference in total morphine consumption and vital data between the two groups while patients were intubated. Our protocol was to start weaning the patients from sedation and prepare for extubation 2 h after admission to CSICU and after ensuring the stable hemodynamic and full return of muscle power, so once these criteria were met, propofol and DEX infusion were turned off, and patients were extubated after full recovery.Our primary outcome was the pain score assessed by the primary nurse and physician immediately after extubation. The pain was evaluated according to the numeric pain intensity scale (NPIS), ranging from no pain (0) to severe non-tolerable pain (10).We reviewed the pain scores and vital signs every hour in all patients for the first 12 h post-extubation in addition to sedation score which was assessed by modified Ramsay score (MRS) and ranged from 1 to 6 as follows: 1 = anxious/agitated, 2 = cooperative oriented, 3 = responds to commands only, 4 = asleep with brisk response to light glabellar tap (LGT), 5 = sluggish response to (LGT), 6 = asleep no response to (LGT).Our protocol was to administer 2–3 mg of morphine to the patient once the pain score is ≥2, and the total morphine consumption in the first 12 h post-extubation in both groups was reviewed, and that was our secondary outcome in addition to the vital data and sedation scores in the first 12 h after extubation.T test was used to compare the continuous variables, and chi-squared test or fisher exact test was used for categorical variables when appropriate. The trend of pain severity was investigated by a repeated measure analysis of variance (ANOVA) model. Freedom from the first dose of morphine was plotted using the Kaplan-Meier survival curve and compared between both groups using a log-rank test.Statistical analysis was performed using SPSS 15 for Windows . Continuous data were presented as mean ± standard deviation and categorical data as count and percent. p = 0.75). The average time of anesthesia was 312 ± 66 min in group (A) and 309 ± 42 min in group (B) (p = 0.54). Patients stayed in the intensive care unit (ICU) after surgery with a mean time of 2.9 ± 1.1 days and a range of 2 to 4 days.One hundred and twenty patients with a mean age of 56 ± 10.1 years were included in the study. The mean left ventricular ejection fraction (LVEF) was 40 ± 9.4% in the DEX group compared to 44 ± 7.3% in group B .Patients experienced a period of analgesia after surgery. The most severe pain had a point that was less than 3. By the 6th hour after surgery, the pain started to appear gradually and became more severe. The severity of pain diminished until the disappearance at the 18th hour after surgery  . The mean arterial pressure had increased in both groups within the first 1 h and dropped within the first 2 h then became stable in the DEX group with a lower heart rate than the other group.The assessment was done every hour during intubation and 2-hourly after extubation; the mean sedation score was analyzed all through intubation Table . We obsep < 0.001, OR = 909, 95% CI 0.05–0.19). Moreover, the dose of received morphine sulfate was lower in the DEX group (1.0 ± 1.2 mg) compared to 2.9 ± 1.8 mg in the other group (p < 0.001).In the DEX group, 10% of patients needed to receive morphine for pain compared to 95% of the patients in the other group (p = 0.09). The pattern of receiving the first dose of morphine sulfate was similar in both groups.The time of prescription of the 1st dose of morphine sulfate could be considered as a proxy for the beginning of intolerable pain (pain score between 4 and 5) Fig. . The paiThis study demonstrated that early infusion of DEX following CABG operations was associated with a reduction of morphine usage, a decrease in pain severity, and improvement of sedation, which encouraged early extubation. Pain control is crucial after cardiac surgery. The release of catecholamine causes the increase of the peripheral vascular resistance, heart rate, and risk of myocardial infarction, arrhythmias, and mortality. From our observations, we noticed a transient rise in main arterial pressure (MAP) during the 1st postoperative hour in both groups, followed by a decrease in MAP.Arain and associates  found a Our findings were in line with Liu and coworkers’  meta-anaOn the other hand, Mukhtar and colleagues  concludep = 0.561 and 0.017, respectively). Barletta and associates [Shehabi and coworkers  found thsociates  stated tsociates  concludeIt worth mentioning that, while 95% of the control group were depended on opioids, 5% only of them only received non-steroidal anti-inflammatory (NSAID), according to the assessment of the post-operative ICU doctors who considered most of these patients with high pain threshold, and so, NSAID was enough to control their pain. Moreover, the dose of opioids given in the DEX group was significantly less than those of the other group , 21.The pattern of pain in both groups was almost the same, which means that DEX does not alter the trend of the pain but decreased the intensity, and both groups needed to receive analgesics at the same point according to pain score between 4 and 5. These results agreed with Cheng and associates’ study .p = 0.512). There are many factors other than pain and analgesics which could influence the ICU stay, including the patient’s hemodynamics, which can be affected by other etiologies other than pain.Some authors mentioned that the use of DEX decreased the length of ICU stay in comparison with the use of other sedative and analgesics like midazolam and morphine, and we did not observe in our study significant differences in ICU stay as it was 2 ± 0.5 and 3 ± 0.1 days (From the clinical point of view, Lin and coworkers  suggesteThe primary limitation of the study is the retrospective nature, and several factors may have affected the outcomes other than the treatment. A randomized clinical trial is required to adjust for the measured and unmeasured variables that could confound the results. However, because the administration of DEX in our cohort was not related to patients’ specific risk factors, the two groups had comparable baseline data.Administration of dexmedetomidine in the early postoperative period can be safe. It may reduce the use of opioids, has sedative, analgesics, and sympatholytic effects that could play a useful role during the management of coronary artery bypass patients, and may improve postoperative recovery.


Total knee replacement is a common operative procedure to improve pain, function, and quality of life in patients with end stage knee osteoarthritis. The current study aimed to compare simultaneous bilateral versus unilateral total knee replacement on pain intensity and recovery of function.A total of 80 patients  aged 63.28 (9.4) years undergone total knee replacement participated in the current study. The participants were admitted for 5–7 days in the hospital. Participants in both the group received similar inpatient and outpatient physiotherapy sessions. Pain intensity and function capacity were assessed at baseline, day 7, and day 30 postoperatively using visual analogue scale and lower extremity functional scale, respectively. Repeated measures analysis of variance was used to analyze the data.p < 0.001) and improvement in the functional capacity  following total knee replacement at 30 days post-operatively. However, there was a non-significant difference noted between bilateral versus unilateral total knee replacement on the reduction of pain intensity  and improvement in the functional capacity  at 30 days post-operatively (p > 0.05).Both groups showed a significant reduction of pain intensity (Day 0, mean 8.9, SD 1.0; Day 30, mean 2.2, SD 1.3 in bilateral total knee replacement; Day 0, mean 8.8, SD 1.1; Day 30, mean 2.0, SD 1.5 in unilateral total knee replacement; Simultaneous bilateral total knee replacement was associated with a similar reduction of pain intensity and recovery of function compared to unilateral total knee replacement, suggesting the use of simultaneous bilateral total knee replacement in patients with bilateral knee osteoarthritis since its costs and rehabilitation process could be reduced compared to staged bilateral total knee replacement. Total knee replacement (TKR) is a common operative procedure to improve pain, function, and quality of life in patients with severe grade knee osteoarthritis (OA) –4. HowevA few studies also investigated differences in pain and physical function following simultaneous bilateral or staged bilateral TKR. While one study indicates functional improvements following simultaneous bilateral TKR , anotherp = 0.01). While a previous study reported significantly better postoperative functional outcomes in simultaneous bilateral TKR group [Many studies also compared perioperative outcomes and functional recovery between simultaneous bilateral versus unilateral TKR. For instance, Hart et al.  reportedKR group , a recenKR group . TherefoIt was a series of prospective TKR cases performed by an Orthopedic surgeon in 3 years 2016 to 2019). This study compared two surgical procedures  on pain and physical function. Pain intensity and recovery of function was assessed at baseline, day 7, and day 30 post-operatively in patients with unilateral and simultaneous bilateral TKR. Institution ethics committee, RRC, King Saud University, Riyadh, Saudi Arabia approved the study. A written informed consent was taken from each patient. Inclusion criteria were as follow: (a) patients with end stage primary OA, (b) bilateral symptomatic knee OA, and (c) patients undergone first time for simultaneous bilateral or unilateral TKR. A total of 80 patients , undergoing TKR, were included in the current study. Patients with cardiopulmonary comorbidities and systemic illness such as chronic obstructive pulmonary disease, diabetes mellitus, cerebrovascular disease, peripheral vascular disease or active coronary artery disease were excluded for simultaneous bilateral or unilateral TKR [ to 2019.Medial parapatellar approach was used for both unilateral and simultaneous bilateral TKR . VanguarParticipants in both the group received similar inpatient  and outpatient  physiotherapy sessions. Inpatient physiotherapy sessions comprised of strength training of lower extremity , mobility exercise, range of motion exercise, and gait training with walker. Outpatient physiotherapy sessions includes strength training of hamstrings, quadriceps, and glutei muscles, mobility exercise, range of motion exercise, and gait training and walking reeducation.Pain intensity and function capacity were assessed at baseline, day 7, and day 30 post-operatively using visual analogue scale (VAS) and lower extremity functional scale (LEFS), respectively. The VAS is a valid and reliable outcome measure to assess both acute and chronic pain –26. VAS p < 0.05 was considered for the statistical significance. The sample size was calculated using G*Power version 3.1.9.4. The required sample size for detecting an effect of 0.25 with 80% power and 0.05 level of significance in comparison of two treatment group  and three level of measurements  was 86. However, in the current study, only 80 patients were included.Data was analyzed using IBM SPSS Statistics 21. The improvement in pain and functional scores during 1-month between simultaneous bilateral versus unilateral TKR were assessed using the repeated measure ANOVA. Two variables for group  and three variables for time (0 day versus 7 day versus 30 day) were used. A value of p < 0.001) (Table p > 0.05)  Table . However5) Figs. .Table 1The current study aimed to compare simultaneous bilateral versus unilateral TKR on pain intensity and recovery of function at 30-days postoperatively. Results of the current study indicated that both groups showed a significant pain relief and improved function after TKR at 30 days post-operatively. There was no significant difference noted between simultaneous bilateral versus unilateral TKR on pain intensity and recovery of function.Some studies indicate that simultaneous bilateral TKR surgery reduces rehabilitation time and have no additional risk for postoperative complications compared to unilateral TKR , 32–35. Recently, a study reported that bilateral simultaneous unicompartmental knee arthroplasty shows better functional recovery at 6 month post-operatively than unilateral TKR , 39. HowTKR is most common and successful surgical intervention to reduce pain and improve function in patients with end stage osteoarthritis , 29, 30.It has been recommended that patients undergo simultaneous bilateral TKR surgery had a prolong rehabilitation, increased length of hospital stay, higher blood transfusion, increased number of painful postoperative days, a greater number of complications, and increased financial burden , 39. NonIt is well established that TKR reduces knee pain and improves physical function in patients with knee OA. In line with previous studies, the current study reported reduced pain intensity and improved physical function in both simultaneous bilateral or unilateral TKR groups. The changes in pain intensity and physical function were statistically and clinically significant and were greater than reported minimally clinical important difference –48. The The current study has several potential limitations. In the current study, physical function was assessed using LEFS, which is a subjective self-report functional scale. An objective outcome measure could be included to assess wide range of physical function. For instance, various performance based outcome measures such as timed up and go test and stair climbing test could be used to better understand functional recovery in these population. Additionally, the current study only assessed pain and function. Other important outcome measures such as ambulation, muscle strength, mobility, range of motion, and quality of life are warranted to consider in future study. The result of this study was restricted to simultaneous bilateral or unilateral TKR in patient with end stage OA, and therefore it might limit the generalizability of findings to other types of replacement surgeries. Additionally, the current study compared simultaneous bilateral TKR with a single unilateral TKR instead a staged bilateral TKR. Therefore, randomized controlled studies are warranted to further identify the differences in the various outcomes between simultaneous and staged bilateral TKR. Moreover, future study may investigate the effect of physiotherapy intervention to reduce post-operative complications and improve functional outcomes after simultaneous bilateral or unilateral TKR.Simultaneous bilateral TKR was associated with similar reduction of pain intensity and recovery of function compare to unilateral TKR, suggesting the use of simultaneous bilateral TKR in patients with bilateral knee osteoarthritis since its costs and rehabilitation process could be reduced compared to staged bilateral TKR.


The prevalence of low back pain with radiculopathy in general population varies from 9.9% to 25%, which can be due to bony narrowing of the lateral recess or due to prolapsed intervertebral disc. Transforaminal epidural injection of a mixture of long-acting anaesthetic (bupivacaine) and particulate steroids (depomedrol) has been a treatment modality in patients not responding to initial physiotherapy and neuropathic pain medications.To analyze the effectiveness of transforaminal epidural steroid injection (TFESI) in the treatment of low back pain with radiculopathy, a retrospective case series evaluating the records of patients that received TFESI (1 mL 0.5% bupivacaine +1 ml/40 mg depomedrol) under C-arm guidance from January 2015 to December 2018 (3 years) at Upendra Devkota Memorial-National Institute of Neurological and Allied Sciences (UDM-NINAS), their lumbo-sacral MRI and the pre-procedure, 1-week and 3-month numeric pain rating scale, were analyzed. Successful treatment  in the patients with bony recess stenosis and those with prolapsed intervertebral disc was compared.t test p value < 0.001) at 1 week post injection and 3.23 ± 3.34  at 3 months post injection. Twenty-six of the 35 patients (75.29%) had more than 50% pain relief compared to baseline at 3 months and were satisfied. Nine patients continued to have pain; however, only one required a surgical intervention. The effectiveness of TFESI was not significantly different in different ages  and in different anatomic levels . Six out of eight patients with bony recess stenosis benefited as compared to 14 out of 19 patients with PIVD, though it was not statistically significant . There were no adverse events recorded.Out of 67 patients that received TFESI, 35 (52.23%) could be followed up. The mean age was 55.8 ± 14.39 years and 51.3% were females. 68.57% had L5 and 20% had S1 radiculopathy. Bony recess stenosis was seen in the aged 40% and PIVD was the cause of radiculopathy in 60%. The median duration of radicular pain prior to intervention was 3 months. TFESI was effective as the mean numeric pain scale before injection was 8.97 ± 1.32 which reduced to 3.91 ± 3.23 (paired TFESI is a safe and efficacious treatment modality in patients with radicular low back pain especially in aged patients in whom surgery under general anaesthesia is not free from risk. Low back pain is one of the most common reasons for absence from work and physical limitation worldwide and affects 80% of the general population at some point in their lifetime , 2. LumbRadicular pain occurs not just due to mechanical compression but due to the release of neurochemical and inflammatory mediators at the target site . EpiduraThis was a retrospective case series of patients that received TFESI for chronic radicular backache from January 2015 to December 2018 in UDM-NINAS, a tertiary care neuro centre in Kathmandu, Nepal. Patients that did not respond to standard initial management, those not willing for surgical intervention and aged patients with risk for microscopic discectomy under general anaesthesia were given the option of targeted lumbar root block. The procedure was carried out by a neurosurgeon or a neurosurgical trainee under direct supervision of a neurosurgeon in the radiology suite of the hospitalThe intervention was done on day-care basis after adequate counselling, consenting and ruling out underlying coagulopathy. Patients were made to lie prone on the radiolucent table after checking for allergy to the iodine dye. Antero-posterior (AP) subpedicular approach was used to deliver the treating medicine in the traditional safety triangle, which is the epidural space just caudad to the inferior margin of the pedicle, immediately superior, lateral and anterior to the targeted exiting nerve , 13. LocTo target the S1 root, the upper end plate of the sacrum was squared off with a cranial tilt of the C-arm and the caudal border of the anterior half of the S1 pedicle passing the needle through the posterior S1 sacral foramen. A lateral fluoroscopic shot is taken to confirm the needle tip close to the floor of the sacral canal but never ventral to it [If the needle tip inadvertently came in contact with the exiting nerve, the patient felt a sharp twitch going down his leg (for which the patient was earlier made aware of), and the tip was slightly withdrawn but the procedure continued as this was a confirmatory sign of vicinity to the exiting nerve.One millilitre of iodine dye was then introduced after re-aspiration to rule out vascular injection and peri-neuro-seathogram analyzed to ascertain perineural flow of dye along with spread of dye in the ventral epidural space. Premixed 1 mL of 0.5% bupivacaine and 40 mg (1 mL) of depomedrol was then gradually injected after re-aspiration to rule out vascular injection again.Immediate effect of the treatment medicine was assured by making the patient walk in the radiology suite. The patient was discharged after observing him/her for 4–6 h post procedure with counselling regarding modification of activities, different exercise, physical therapy and follow-up 1 week post procedure.Information of all patients who received TFESI from January 2015 to December 2018 was retrieved from the operation theatre record book and further information of imaging findings and contact number from the hospital electronic record system. A performa for the telephonic inquiry had been made and agreed by the authors. An independent assessor, here author LS, contacted the subjects by phone and performed standardized interview to determine the outcomes. Numeric pain rating scale (NPRS) from 0 to 10 was used to characterize radicular pain before TFESI, at the end of the first week and 3 months following the procedure. The duration of pain relief, the need for another TFESI and the need for surgical intervention at any point in time or any inadvertent complications as limb weakness infection were enquired. Improvement in the numeric pain score by more than 50% of the baseline at 3 months post TFESI was regarded as a successful intervention.p value of < 0.05 was taken as statistically significant.The records of MRI images were reviewed by a consultant radiologist, here author PA, where the cause of the radiculopathy was differentiated mostly by prolapsed intervertebral disc or by the bony narrowing of the lateral recess. The outcome of the intervention in these two subgroups at 3 months compared. Chi-squared test (Fischer’s exact test) was done to evaluate the outcome in these two categories, and a T test was used to compare the pre-procedure, 1-week and 3-month NPRS, and a p value of < 0.05 was taken as statistically significantA master table was made in the Statistical Package for the Social Sciences  which was used for analyzing frequency distribution and all statistical analysis  of these patients could be contacted for telephonic interview by the independent assessor; hence, analysis as a whole was confined on these 35 patients.The mean age was 55.8 ± 14.39 years, with the youngest being 32 years and the oldest being 80 years. Aged patients in whom surgical intervention could not be offered following failure of conservative treatment due to risks of general anaesthesia were given the option of TFESI; 10 (28.57%) of the 35 patients were 70 years and above. There was no sex predilection in the treated population with 51.3% being females.Regarding the level of involvement, 68.57% of patients had involvement of the L5 root due to pathology at the L4–L5 level and 20% had S1 radiculopathy due to pathology at L5–S1 level. In two patients, the L4 root was involved and in two (5.71%), both L5 and S1 were involved. Only these two patients received TFESI at two levels, the rest at a single level. Nearly half (17 of 35) of the patients had the left side affected, the rest 18 had a right-sided involvement.The median duration of symptoms of radicular low backache after which the patient received TFESI was 3 months with interquartile range 11 months. TFESI was not offered to patients with radicular symptoms less than a month. The maximum duration of radicular pain after which TFESI was done was 8 years.To assess the effectiveness of the TFESI, a numeric pain rating scale from 0 to 10 was used. The numeric pain rating scale for the radicular pain was recorded before the intervention. The mean numeric pain rating scales before the intervention, at the end of 1 week and after 3 months along with the standard deviations were as follows . There were no adverse events recorded.A successful intervention has been defined as the reduction of radicular pain by more than 50% of baseline at 3 months following TFESI. Twenty-six of the 35 patients (75.29%) had more than 50% pain relief compared to baseline at 3 months and were satisfied. Nine patients continued to have pain; however, only one required a surgical intervention. Twelve out of 14 patients with bony recess stenosis benefited as compared to 14 out of 21 patients with PIVD, though it was not statistically significant (Fischer’s exact test In 9 (25%) patients out of 35, TFESI was not effective. In all of these 9 patients, the numeric pain rating scale was not reduced adequately at 1 week post injection, though all patients responded to TFESI immediately. Only one of these patients required surgery and the rest continued other forms of conservative management.There were no major complications in this limited series as epidural hematoma, infection or arterial injection as sterility was paid attention to and aspiration before injecting the medication was done routinely. Some patients, however, felt dizzy when made to walk after the injection which improved on its own after they rested supine for some time. It was a routing to keep the patients in the hospital for 4 h for observation after the injection.Aged patients with sciatica cannot be treated with microscopic discectomy when the initial conservative measures fail due to the risks of general anaesthesia. We evaluated the efficacy of TFESI in this subgroup Table .Table 2Nine (90%) of 10 patients that were ≥ 70 years responded well with TFESI compared to only 68% in the younger subgroup as they had a reduction in numeric pain rating scale by more than 50% at 3 months. This however was not statistically significant.On a technical note, the trajectory to block the L5 root differs from that to block the S1 route as has been discussed in the methodology section. To analyze if this difference affected the outcome, the outcome of patients who underwent singular L5 or S1 root block were analyzed. Four patients (two where L4 root were blocked and two where both L5 and S1 were blocked) were excluded from the analysis Table .Table 3Only four (57.14%) of the seven patients with S1 problem benefited at 3 months compared to 19 (79.17%) of the 24 patients; this, however, was not statistically significant.We tried to evaluate the effectiveness of TFESI in the two subgroups where the radiculopathy was due to bony recess narrowing or due to prolapsed intervertebral disc. For this, an independent Consultant radiologist reviewed all MR imaging of the lumbo-sacral spine and decided which of the two the cause of radiculopathy in the patients was. There were patients who had bony recess narrowing as well as some PIVD. It was under the jurisdiction of the radiologist to decide which the more important cause in these scenarios was. Of the 35 patients who could be interviewed, we could retrieve 27 (77.14%) MRI lumbo-sacral spine records.p value (independent sample t test) was 0.175, though the mean age of patient with bony narrowing of the lateral recess was higher.The mean age of patients in whom PIVD was the cause of radiculopathy was 53.37 ± 13.28 years (19 patients) compared to 61.5 ± 15.1 years (eight patients) in whom bony narrowing of the recess was the cause. Our presumption that older patients tended to have more of bony narrowing of lateral recess was however proven wrong as To evaluate the effectiveness of TFESI in these two subgroups, a chi-squared (Fisher’s exact) test was done. The following is the tabulation Table .Table 4Fourteen (73.68%) out of 19 patients who had a PIVD continued to have improvement at 3 months compared to 6 (75%) of patients with bony recess stenosis. The outcome was comparable in the two subgroups, and TFESI was not selectively better for one subgroup or the other.Back pain is the fifth most common reason individuals seek medical care in USA, and annually, 30 to 50 billion dollars is spent on healthcare to treat it annually . The subTFESI is an effective form of minimally invasive treatment in patients with unilateral radicular pain due to herniated lumbar disc or spinal stenosis . In the In the transforaminal approach, there are two commonly practiced techniques, the anterior-posterior subpedicular approach and oblique Scotty dog subpedicular approach. Kaliya-Perumal and colleagues have highlighted in details the procedural steps of both the approaches . To reduThey have stressed the danger of superior and anterior position of the needle tip during TFESI. Keeping this dreaded complication in mind, we avoided the needle tip position medial to the middle of the pedicle and always aspirated before injecting the particulate steroids.The agent used for this intervention, however, is highly debated. Ng and colleagues randomized patients indicated for TFESI to get methyl prednisolone and bupivacaine or bupivacaine alone. There was no difference in the outcome at 3 months . A systeLeung and colleagues  have pubKennedy and colleagues  followedAdiley and colleagues  comparedTFESI can be effective in treating radicular backache so much so as to avert the need of a surgical intervention. The premise is that once the acute pain is taken care of, the patient continues physical therapy, activity modification to strengthen the paraspinal muscles and hence prevent further recurrences. The result of the NERVES trial by Wilby and colleagues  is highlOur study has a few limitations. It is a depiction of the early outcome following TFESI and we need to further follow up our patients for a longer duration to establish the efficacy. Manchikanti and colleagues have highlighted the short-term efficacy of this technique; however, the evidence of the long-term efficacy is only moderate . In our TFESI is a safe and efficacious treatment modality in patients with radicular low back pain especially in aged patients in whom surgery under general anaesthesia is not free from risk. The relief from the activity limiting radicular pain gives the patient opportunity for further exercising and strengthening the low back muscles so as to avert the need of surgical intervention.Additional file 1. Master Table.


No important differences in the PROMs were found between EDS and HMS. Women were represented in > 90% of EDS/HMS cases and fibromyalgia cases, and in about 64% of the other groups. The EDS/HMS group was significantly younger than the others but had a longer pain duration. The pain intensity in EDS/HMS was like those found in spinal pain and WAD; fibromyalgia had the highest pain intensity. Depressive and anxiety symptoms were very similar in the four groups. Vitality—a proxy for fatigue—was low both in EDS/HMS and fibromyalgia. The physical health was lower in EDS/HMS and fibromyalgia than in the two other groups. Patients with EDS/HMS were younger, more often female, and suffered from pain for the longest time compared with patients who had localized/regional pain conditions. Health-care clinicians must be aware of these issues related to EDS/HMS both when assessing the clinical presentations and planning treatment and rehabilitation interventions.Although chronic pain is common in patients with Ehlers–Danlos syndrome (EDS) and hypermobility syndromes (HMS), little is known about the clinical characteristics of these groups. The main aim was to compare EDS/HMS with common local and generalized pain conditions with respect to Patient Reported Outcome Measures (PROMs). Data from the Swedish Quality Register for Chronic Pain (SQRP) from 2007 to 2016 ( Ehlers–Danlos syndrome (EDS) is a heritable condition characterized by a disorder in the collagen, causing increased laxity in bodily organs such as skin, ligament, joints, blood vessels, and inner organs . As a coChronic pain, a major problem both in EDS and HMS, is found in up to 90% of patients with hypermobile EDS ,14. The To date, there are few comprehensive studies of the self-reported clinical situation for patients with EDS/HMS and a lack of knowledge of how the clinical picture  relates to other common chronic pain conditions representing local and generalized pain conditions. This knowledge gap has motivated this study of chronic pain patients based on Patient Reported Outcome Measures (PROMs) from the Swedish Quality Registry for Pain Rehabilitation (SQRP). The SQRP offers an opportunity to investigate PROMs as most relevant specialist care units throughout Sweden deliver data to the SQRP. Hence, this study compares EDS/HMS with common local and generalized chronic pain conditions/diagnoses with respect to PROMs such as pain aspects, emotional distress, life impact, and health-related quality of life (HRQoL) in large cohorts of patients.This study uses data obtained from the SQRP as most Swedish chronic pain clinics (>90%) refer data from the SQRP to assess patients and to develop interdisciplinary rehabilitation strategies. Typically, primary care physicians refer patients to these specialist clinics because the patients present with complex chronic pain. Patients complete the SQRP questionnaires on up to three occasions: during their first visit to the clinic (baseline); immediately after completing an interdisciplinary rehabilitation program; and at a 12-month follow-up. Not all patients participate in interdisciplinary rehabilitation programs and therefore do not report their situation on the second and third occasion. This study uses data from the first visit (baseline) only.The study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice and approved by the Ethical Review Board in Linköping (Dnr: 2015/108-31). All participants received written information about the study and gave their written consent.The SQRP consists of several validated instruments that include questions about pain, psychological distress, perceived health, occupational status, and other demographic information. Since the SQRP’s inception in the 1990s, a few changes have been made; however, for the period from which data for this study were extracted (May 2007 to April 2016), no meaningful changes were made to the registry. This study uses measures similar to the recommendations by the IMMPACT group concerning outcomes in chronic pain trials .The data set include age of the participant (years), gender , educational background (either college/university degree or not), and full-time employment status (yes or no). In addition, the dataset included how many times a patient visited a physician during the last year .NRS-7 days.A Numeric Rating Scale (NRS) was used to rate average pain intensity for the last week, with a possible score from 0 to 10 where the highest number represents worst possible pain. This variable is denoted as MPI Pain Severity (range 0–6). MPI is a 61-item questionnaire that measures the impact of chronic pain [Pain intensity was determined using the Multidimensional Pain Inventory (MPI)—nic pain . The curnic pain . Persistent Pain. In addition, the duration of chronic pain (years) was included—Pain Duration.A single question about whether the pain is persistent or recurrent (yes or no) was also included—Number of pain regions  was obtained using 36 predefined anatomical areas (18 on the front and 18 on the back of the body), and the patients registered the areas where they experience pain: (1) head/face, (2) neck, (3) shoulder, (4) upper arm, (5) elbow, (6) forearm, (7) hand, (8) anterior aspect of chest, (9) lateral aspect of chest, (10) belly, (11) sexual organs, (12) upper back, (13) low back, (14) hip/gluteal area, (15) thigh, (16) knee, (17) shank, and (18) foot. The number of areas with pain (range: 1–36) were summed. For the current period in the SQRP, there was no option for indicating missing values for this variable, resulting in 4.5% of the participants indicating that they did not have any painful region of the body.HADS) [HADS-A) and seven the depression subscale (denoted HADS-D). Each item is scored between 0 and 3 with possible scores range from 0 to 21. Higher scores indicate more problems: a score of 7 or less on each subscale indicates a non-case, 8–10 indicates a possible case, and ≥11 indicates a definite case of anxiety/depression. The Swedish version of the instrument has sound psychometric properties [MPI Distress (range 0–6)—was also used. Among these variables were a subscale of SF-36 (see below). Fatigue is a common complaint associated with EDS and HMS, so the SF36-Vitality subscale was included as a proxy for fatigue.Symptoms of anxiety and depression were measured using the Hospital Anxiety and Depression Scale (HADS) , a 14-quoperties . The MPIMPI Interference, MPI Control, and MPI Activity. MPI Interference measures interference of pain on one’s life, MPI Control measures the amount of perceived control of one’s life situation, and MPI Activity, measured using the General Activity Index of the MPI, measures one’s activity. These three subscales all range from 0 to 6.Within this area, three MPI variables were chosen: SF36) is a multidimensional health concept that measures several facets of health and well-being [SF36-PCS) and a mental component summary (SF36-MCS). This study uses both the SF36-PCS and the SF36-MCS.Widely used and with a validated Swedish translation, the Short Form Health Survey  was included . The SQRp2) as suggested by Cohen [p-values in the context of multiple comparisons. The first part  for descriptive analysis and group comparisons. We compared the different groups using a series of one-way ANOVAs. For categorical variables, dummy coding was performed followed by chi-square tests. As we did not assume equal variance between groups, Welch’s ANOVA, rather than Fischer’s, is reported. Effect sizes were calculated for the partial omega-squared statistic and the comparisons between EDS and HMS Cohen’s d are presented. For post hoc tests, we used the Games-Howell statistic. We employed the standard descriptions for ANOVAs of small (0.01–0.059), medium (0.06–0.139), and large (>0.14) effect sizes  present a risk of downplaying the interrelationships among different factors and therefore reaching incorrect conclusions. Classical methods also assume variable independence when interpreting results and it can be risky to consider one variable at a time. If multicollinearity  occurs among the X-variables, the regression coefficients become unstable and their interpretability breaks down. Hence, we used advanced multivariate data analysis (MVDA)—i.e., Principal Component Analysis (PCA)—for the multivariate correlation analyses to detect outliers and Orthogonal Partial Least Square Regressions-Discriminant Analysis (OPLS-DA) for the multivariate regressions of diagnoses. These analyses were performed using SIMCA-P+  . SIMCA-P2 and distance to model in X-space. R2 describes the goodness of fit—the fraction of sum of squares of all the variables explained by a principal component. Q2 describes the goodness of prediction—the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods.As outliers can markedly bias regressions, PCA was used to check for multivariate outliers. Outliers were identified using two methods: score plots in combination with Hotelling’s T2, Q2, and the result  of a cross-validated analysis of variance (CV-ANOVA). In the present study, we required significant CV-ANOVA for a regression as a whole to be significant. A certain variable within a regression was considered significant when VIP > 1.0.OPLS-DA was used to explore which variables in the multivariate context differentiated EDS from the three other diagnoses; in these three regressions, EDS was denoted 1 and the other diagnoses were denoted 0 for the three comparisons. The variable influence on projection (VIP) indicates the relative relevance of each X-variable. VIP ≥ 1.0 was considered significant if the VIP value had a 95% jack-knife uncertainty confidence interval non-equal to zero. P(corr) was used to note the direction of the relationship (positive or negative). P(corr) depicts the loading of each variable scaled as a correlation coefficient with a standardized range from −1 to +1. For each regression, we report the RFirst, we wanted to determine whether there were any differences between patients with EDS and patients with HMS (step 1). Second, we wanted to determine whether there were potential differences between patients with either of these diagnoses and other common diagnostic groups of patients referred to specialist pain clinics (step 2). In the final step (step 3), we analyzed to what extent EDS multivariately differentiated from the three other diagnoses and which variables were important for these differences between diagnoses.n = 40,518), 427 patients were classified as with EDS and 420 patients were classified as with HMS. Since pain is a criterion for EDS hypermobility type we assumed that most of those patients belonged to this sub-type. As there was a potential for lack of precision in differential diagnosis between these related diagnoses, we looked for any systematic differences between these groups on the measures included in the study. No statistical differences (excluding one variable) between the two diagnoses were found . In addition, no significant differences between the two groups for the categorical background variables , health-care consumption and persistent pain were revealed. Because the two groups exhibited similar results for the investigated variables, we clustered the two groups together in the further analysis (denoted EDS/HMS), resulting in a group of 795 patients (1.9% of the patients in SQRP) as some with EDS had a secondary diagnosis of HMS.There was a significant difference on the SF36-PCS—i.e., patients with EDS scored somewhat lower  than patients with HMS  (t = (687.29) 3.50 spinal pain. A more localized pain condition related to trauma—i.e., whiplash associated disorders (WAD)—was also included (n = 14 203): spinal pain (n = 7183); fibromyalgia (n = 5791); WAD (n = 1229); and EDS/HMS (n = 795).To explore differences between patients with EDS/HMS and patients with other common conditions in the SQRP, we compared the EDS/HMS group with patients who had a main diagnosis of fibromyalgia, an approach used by previous research . In addiincluded . TherefoFemale gender was more common for EDS/HMS (93.6%) and fibromyalgia (95.1%) . Age wasWAD had the highest proportion with high education (29.1%) and EDS/HMS (25.5%), whereas patients with fibromyalgia had the lowest proportion (19.8%) . Workingp < 0.0005). The EDS/HMS group had almost as much spread of pain on the body  as the fibromyalgia group (mean: 19.49 vs. 22.28). The WAD group had 7.62 and the spinal pain group had 8.33 fewer sites than the EDS/HMS group   .p < 0.0005) and WAD was intermediary.For the anxiety subscale of the HADS, there were significant group differences . On a grFibromyalgia had the highest scores on MPI Interference (mean: 4.61) and without significant differences between EDS/HMS and the two other groups (4.32–4.43). The worst situation also existed for fibromyalgia (mean: 2.40) with respect to MPI Control. EDS/HMS and WAD were intermediary (both 2.59) and the best situation was found for the spinal pain group (2.81). MPI Activity only showed trivial differences across the four groups.p < 0.0005). The three other variables within this area—SF-36 MCS, EQ-5D index, and EQ-VAS—showed significant differences, but the effect sizes were small.SF-36 PCS was associated with a large effect size . There wIn the next step, we used the variables under investigation to multivariately investigate  whether there were significant differences in the clinical presentations between EDS/HMS and the three other diagnoses . Number 2 and Q2 were both 0.09). The variables that significantly differentiated EDS/HMS from fibromyalgia were age, two pain intensity variables (NRS-7days and MPI Pain Severity), depressive symptoms, and SF36-MCS . Hence, 2 and Q2 were low (0.13).In the multivariate context, variables that significantly contributed to differentiate spinal pain from EDS were female gender, age, pain duration, SF36-PCS, and SF36-Vitality . Hence, The strongest regression was obtained when multivariately differentiating between WAD and EDS/HMS . Pain duThis study reveals several overlapping as well as condition-specific impacts of chronic pain for patients with EDS/HMS, fibromyalgia, spinal pain, and WAD. Six variables showed significant differences with large effects sizes—age, pain duration, number of pain regions, MPI Pain Severity, SF36 -Vitality, and SF36-PCS) . CompareWe did not find any important significant differences between patients with EDS and patients with HMS diagnoses . HMS andThe patients with EDS/HMS were younger and had the longest pain duration. This result is expected as EDS/HMS is a genetic disorder that debuts in childhood, and its consequences, including pain, increase as patients age . Women wCompared with patients who had spinal pain or WAD patients, fibromyalgia and EDS/HMS patients reported significantly more painful sites. This is expected since both criteria for fibromyalgia and EDS/HMS require spreading of pain. Widespread pain, a feature of several chronic pain disorders , negativThe MPI scale Pain Severity, which measures perceived severity and intensity of pain, was rather high for all diagnostic groups, but the fibromyalgia group scored significantly higher. A similar pattern was found for the other pain intensity variable NRS-7 days, confirming results from previous research . WhetherFatigue is one of the main explanations for disability among EDS patients . AlthougAlthough the fatigue reported by EDS/HMS patients has usually been related to chronic pain and its consequences such as muscle weakness ,56 and kThere is an increasing amount of evidence pointing toward a high prevalence of psychiatric conditions among individuals with ED/HMS in general and anxiety disorders in particular . However2-value of 0.29. This finding was perhaps not that surprising considering the different pathways to a pathological status between these diagnoses. The clear differences only existed for variables such as duration of the condition, age, sex, and physical quality of life. Therefore, although these diagnoses might be considered to be very different, the patients who seek specialized health-care for these diagnoses in many aspects are quite similar—at least when considering how they self-rate their own health status.The results from step 3 highlighted several differences and similarities between the groups. The overall largest differences existed between WAD and EDS/HMS, with and RThis study’s main strength is its large cohort of patients: 795 patients with either EDS or HMS. To the best of our knowledge, this study is one of the largest studies of these diagnoses. In the SQRP, the proportion of EDS/HMS patients was 1.9%, somewhat smaller than the estimated proportion of 3% for the general population . This diOur findings indicate that EDS/HMS patients referred to pain rehabilitation specialist clinics have complex pain conditions affecting broad aspects of their life, the reported long duration of pain might have contributed to the generalized pain condition similar to fibromyalgia. Persons with EDS/HMS might have an early onset of pain. These results point at the importance of clinical awareness e.g., in primary care that young persons with EDS/HMS are at risk of developing a chronic pain condition.The results also indicate that assessment needs to address not only medical diagnosis, but also pain, function, activity, and participation. Interventions that consider all these aspects to prevent or treat negative long-term consequences might be needed. Relatively complex interventions  may be necessary to improve the patients’ global situation ,63,64.Our results point out that EDS/HMS is associated with a consistent burden of disease like that of fibromyalgia and partially worse than spinal pain and WAD. According to the multivariate analyses of self-reports, there is not a very distinct clinical presentation for EDS/HMS. Moreover, broad impact of chronic pain on daily life was noted for the group of patients with EDS/HMS. Health-care clinicians must be aware that complex rehabilitation interventions might be necessary to improve their patient’s global situation.


Context and objectiveOpioids have heterogeneous side effects including a well-known effect of sedation; however, the opposing effect of stimulation, or somatic activation, has been largely ignored or overlooked. The objective of this study is to determine the prevalence of opioid-induced somatic activation (OISA).MethodsWe conducted a retrospective chart review of 189 patients seen by a single clinical psychiatrist/pain specialist. During the initial encounter, the clinician took a standardized history of every opioid currently or previously taken by the patients, and enquired if the patients had experienced a somatically activating or sedating effect per opioid.ResultsPatients recalled an average exposure to 5.1 opioids (SD: 1.9). Ninety-one patients  reported somatic activation, while 118  reported sedation from at least one opioid. Fifty-eight patients (30.7%) identified at least one opioid as activating, and another as sedating. The distribution of OISA did not significantly differ by gender, race, primary pain diagnosis, or depression. The distribution of OISA by oxycodone significantly differed compared to morphine sulfate , while sedation did not .ConclusionsIn this study, we quantified the previously unstudied phenomenon of OISA. This phenomenon appears dependent on opioid type with some opioids, such as oxycodone, appearing more likely to have this effect. Given current concerns about the risks of opioids in high-risk populations, future studies are needed to study this phenomenon to arrive at an accurate determination of the potential risks and benefits of OISA. In 2016, 50 million adults in the US were reported to be affected by chronic pain, a debilitating and complex medical condition that is increasingly difficult to manage during an opioid-use disorder and overdose crisis . The mosOpioids have a heterogeneous set of effects, with the individual patient and pharmacologic characteristics influencing the patient experience. For example, individuals carry different genetic predispositions for opioid-use disorder, and genetic polymorphisms can affect the pain experience ,7. AdditSedation is a well-known opioid effect; however, the opposing effect of stimulation has been largely ignored or overlooked . In our The purpose of this study is to quantify the proportion of patients with chronic pain who have had the subjective experience of OISA and determine if the likelihood of OISA varied with patient factors or opioid class. Through this investigation, we aim to inform clinical decision-making about prescribing opioids to reduce a patient’s illness burden. We also hope that our findings can guide future studies on this topic.We conducted a retrospective chart review of new patients seen by a single clinical psychiatrist and pain specialist (author S.D.P.) at the Medical Pain Service (MPS) of the Duke Pain Medicine outpatient clinic in Durham, NC from January 2014 through December 2015. The MPS specializes in the treatment of complex pain patients with psychiatric comorbidities. This research was approved by the Duke University Institutional Review Board, permitting analysis of electronic health records with a waiver of consent (Pro00102929). The chart review focused solely on the medical notes of the initial patient encounter. We extracted information including age, sex at birth, primary pain diagnosis, a current or prior diagnosis of major depressive disorder (MDD), and opioid-use history. Primary pain diagnoses were categorized as follows: cervical-spinal or lumbar-spinal pain, sickle cell disease, fibromyalgia, complex regional pain syndrome (CRPS), and other . Due to the patient complexity at the MPS, only the primary pain diagnosis was recorded, even when multiple pain-related comorbidities existed.The standardized opioid history included each unique opioid currently or previously taken. For each opioid, the clinician asked if the patient recalled experiencing an activating or sedating effect. The verbal questions generally included: “Does this medication make you tired? Does this medication give you energy or wake you up at all?” When a patient was equivocal, follow-up questions included: “Do you get up and do more an hour after taking it? Do you talk more? Does your mind move faster? Does it bother your sleep? Do you take it to get going in the morning?” When reporting enhanced function, patients were asked to clarify if they were more functional due to pain relief or a perceived change in energy level. If a patient reported that they could do more due to a lower pain level, described the opioid’s effect as euphoric, or could not differentiate feelings of somatic activation from euphoria, they were not classified as being somatically activated. When conducting chart review, we coded the response for each opioid as follows: sedating, somatically activating, neutral, equivocal, or unknown. For analysis, we collapsed these codes to the following: sedating, somatically activating, or neither .We performed statistical analyses in R statistical software version 3.5.1  . CompariThe 189 patients included 85 males and 104 females; the average age was 46.1 years (Table There were 100 patients with a diagnosis of MDD (53%), and the distribution of activation (p: 0.33) and sedation (p: 0.56) did not significantly differ by MDD status. At the initial encounter, 138 patients (73%) had a documented psychiatric comorbidity of MDD, bipolar, attention deficit hyperactivity, borderline personality, post-traumatic stress, or generalized anxiety disorders. Patients recalled a mean exposure to 5.1 opioids (SD: 1.9). Ninety-one patients (48.1%) had a patient-reported outcome of somatic activation, identifying 1.6 activating opioids on average. In contrast, 118 patients (62.4%) reported at least one sedating opioid, identifying 1.7 sedating opioids on average. Additionally, 58 patients (30.7%) identified at least one opioid as activating, while identifying another as sedating.Exposure to at least one oxycodone formulation was documented for 176 patients, with a mean exposure to 1.4 formulations. Of the 176 oxycodone-experienced patients, 48 (27.3%) reported somatic activation and 51 (29.0%) reported sedation. This included seven (4%) reporting activation and sedation depending upon oxycodone formulation. In contrast, 123 patients had exposure to at least one formulation of morphine sulfate with a mean exposure to 1.1 formulations. Of these 123, 11 (8.9%) reported activation, 30 (24.3%) sedation, and none reported variable activation and sedation. The distribution of somatic activation by oxycodone compared to morphine significantly differed (p: 0.005), while sedation did not (p: 0.46).We reported on a previously unquantified observation of OISA. Nearly half of our cohort recalled experiencing somatic activation while taking an opioid, and the distribution of activation did not significantly differ by gender, race, primary pain diagnosis, or depression. While placebo effects are common in pain medicine, the statistically significant three-fold difference in activation by oxycodone vs. morphine sulfate, contrasted with equivalent rates of sedation, suggests that this is not a placebo effect or sampling artifact .Clinical applicationsIdentifying and understanding OISA is clinically relevant due to potential patient harm from sleep disturbance and hyperactive delirium, and potential benefit from increased functional capacity. OISA can include sleep disturbance, which is concerning due to the high incidence of comorbid sleep disorders among patients with chronic pain and the finding that decreased sleep can increase pain ,22. FurtThese findings may be directly translated to improve clinical care and opioid prescribing practices. We believe that eliciting a patient’s past experiences with opioid-induced energy changes prior to prescribing an opioid, and again on follow-up, should become standard practice. This baseline history can inform treatment decisions, such as transitioning patients with sleep disturbance from oxycodone to morphine formulations when appropriate, or changing opioid formulation if a patient’s OISA manifests with irritability. When a patient has gained functional capacity via somatic activation, caution should be taken when changing opioid dose or formulation since changes in somatic activation can impact functional assessment outside of the patient’s pain report. Further, dose reduction can be difficult in patients experiencing somatic activation due to loss of stimulation, which can be mitigated by replacing this effect with another agent . Such an approach can make opioid reduction easier in an era of tightened prescribing practices ,26.Limitations and future directionsThis study was limited by being a retrospective chart review of patient-reported outcomes documented by a single clinician without a standardized assessment tool. Data interpretation may have been confounded by multiple formulations of an opioid being prescribed to a given individual, as opposed to standardizing treatments with generic oxycodone, generic morphine sulfate, etc. Additionally, no data existed to identify the presence of dose-dependent effects. Finally, while we believe the mental health comorbidities of this cohort are generally representative of real-world patients, the naturalistic nature of this study complicates interpretation.The next step will include delineating clear criteria for OISA so that assessment tools incorporating somatic activation can be developed and validated. Assessment tools will then allow investigations of the relationship between somatic activation and analgesia, i.e., whether suppression of pain leads to a subjective feeling of energy or, conversely, whether somatic activation affects the pain experience. When conducting this analysis, it will be important to determine if the direction of this relationship is homogenous or heterogeneous among patients. From this understanding, drivers of activation can be investigated. For example, catechol-O-methyltransferase single nucleotide polymorphisms known to be protective against sedation among patients taking morphine, while appearing insensitive to oxycodone, can be studied in relation to the differential activation and sedation documented here ,28. FinaThe statistically significant three-fold difference in activation by oxycodone vs. morphine sulfate, contrasted with equivalent rates of sedation, suggests that the patient-reported OISA is not a placebo effect or sampling artifact. The results of this study can be used for improving clinical care practices, such as transitioning patients with sleep disturbance from oxycodone to morphine formulations when appropriate, or changing opioid formulation if a patient’s OISA manifests with irritability. Prospective data are needed to further define and quantify OISA, due to its clinical relevance relating to potential patient harm from sleep disturbance and delirium, and potential benefit from increased functional capacity.


The distraction interventions continued for three consecutive sessions and the numeric rating scale of pain severity was used for data collection. Descriptive and inferential statistics were used for data analysis using SPSS. It was found that pain severity significantly reduced after the distraction interventions in either the auditory or visual distraction groups and also after all three distraction sessions (p = 0.001). However, visual distraction had a better effect on the reduction of pain severity. Therefore, while both visual and auditory distractions reduced pain severity in older patients undergoing hemodialysis, visual distraction was more effective. Nurses are encouraged to incorporate visual distraction as a safe and non-pharmacologic technique into routine nursing care for reducing older patients’ suffering and improving their wellbeing when fistula cannulation is performed.Pain associated with fistula cannulation is a challenge for nurses who provide care to older patients undergoing hemodialysis. Several non-pharmacological methods have been suggested for relieving fistula cannulation pain, but the benefits of visual and auditory distraction methods among older patients undergoing hemodialysis have not been investigated yet. Therefore, this study aimed to compare the effects of visual and auditory distractions on fistula cannulation pain among older patients undergoing hemodialysis. This randomized controlled clinical trial was conducted on 120 older patients undergoing hemodialysis. They were randomly assigned to three groups of visual distraction, auditory distraction, and the control ( Arteriovenous fistula (AVF) is used to create a persistent vascular access for patients undergoing hemodialysis . These pNon-pharmacological pain management during the insertion of a needle into AVF can improve quality of life in older patients and persuade them to continue hemodialysis . DiffereThe effectiveness of distraction in the reduction of the feeling of pain during needle-related procedure among children and adolescents has been reported . FurtherThis randomized controlled clinical trial was conducted between July 2017 and December 2017 in a hemodialysis unit at a hospital located in an urban area of Iran.The sample size based on the result of a previous study , α = 0.0Participants were selected based on the following criteria: age over 60 years; at least two months passed from the installation of AVF; undergoing hemodialysis three sessions per week and each session lasting for 4 h; no history of verbal disturbances; no addiction or drug dependence to pain medications; no history of mental health diseases; and ability to pass the abbreviated mental test (AMT) indicating their cognitive health.The following were considered exclusion criteria: unwillingness to continue with the study; unsuccessful AVF cannulation at the first try; use of tranquilizers in the last 8 h; failure to attend more than two distraction sessions due to referral to another healthcare center; kidney transplantation and death; the presence of pain in other areas of the body based on the older patient’s report; presence of infection and obstruction of fistula based on the nurse’s inspection; and the presence of auditory and visual disturbances.n = 40 in each group)  created the random allocation sequence and the main researcher (MGA) assigned the participants to the groups (h group) . The natThe older patients undergoing hemodialysis filled out the demographic data form and the AMT questionnaire. In addition, the numeric rating scale of pain severity was completed by the participants before commencing the distraction interventions. For illiterate older patients, the main researcher (MGA) read the questions aloud and recorded their answers.This consisted of questions about the older patients’ age, gender, marital status, employment status, literacy status, living status, job status, and history of hospitalization.Older patients suffering from cognitive disorders were identified using the AMT as an instrument to identify any change in their cognitive function. Score 1 was given to each correct answer and score 0–3 suggested a severe impairment, 4–7 a moderate impairment, and score ≥8 suggested a normal cognitive function . The perThis is numbered between 0 and 10 indicating positive and negative pain statements, respectively. Accordingly, the rating of this scale was 0 (lack of pain), 1–3 (low pain), 4–6 (moderate pain), 7–9 (severe pain), and 10 (very severe pain). The Cronbach’s alpha coefficient for this tool was reported as 0.95  and its ®) in a manner that was easy for the older patient to watch while they were lying on the bed. The fistula area was then disinfected by cotton and alcohol (70%) and AVF cannulation by the needle for hemodialysis : 150/300, OD: 1.65, Soha®, BNO: P948115 A MFG) was carried out, while the distraction intervention continued.Initially five min before starting hemodialysis, natural and eye-catching images consisting of the images of sea, birds, and animals were broadcasted through a video display device on a laptop monitor  and an MP3-player (Sony ®) considering a 25–50 dB sound volume calibrated by an audiologist. The AVF area was disinfected by cotton and alcohol (70%) and the AVF cannulation needle : 150/300, OD: 1.65, Soha®, BNO: P948115 A MFG) was inserted. After fixing the needle, the severity of pain felt by the older patients during AVF cannulation was evaluated by a staff nurse who was not a member of the research group. The distraction technique was continued for three consecutive hemodialysis sessions.Listening distraction was started five minutes prior to hemodialysis, and the older patient listened to the selected sounds from nature such as a flowing river, waterfall, walking through the forest, sea, and bird songs using headphones , the pain severity was recorded by a staff nurse who was not a member of the research group.The older patients received routine care during three consecutive hemodialysis sessions. After fixing the AVF needles : 150/300, OD: 1.65, SohaTo reduce variations in performing AVF cannulation and related bias affecting the research outcome, it was conducted by the first author (MGA), who was the hemodialysis nurse in both the control and intervention groups.x2 test were used for data analysis via SPSS version 20 . One-way ANOVA test and x2 test were used for between-group comparisons. To assess statistically significant differences in pain severity between the groups, the Kruskal–Wallis test was used. In addition, the Mann–Whitney U test was used to conduct between-group comparisons of pain severity. The Cohen’s d test estimated the effect size of the distraction interventions on pain severity. The Levene’s test and the Kolmogorov–Smirnov test assessed equality of variances. In addition, p < 0.05 denoted statistical significance.Descriptive statistics including frequency, percentage, mean and standard deviation, and inferential statistics such as one-way ANOVA test, Levene’s test, Mann–Whitney U test, Kruskal–Wallis test, and This research was approved by the ethics committee affiliated with the university in which the third author (NR) worked (decree code: P/A/33/93). The purpose of this study was completely explained to the older patients and a written informed consent form was signed by them. They were assured that the collected data would be used only for research purposes and that they could withdraw from the study at any time without any effect on their care. The research protocol was registered on the website of the clinical registry trial under the code IRCT201709047529N14.x2 test showed no statistically significant differences between the groups in terms of age, gender, marital status, literacy status, marital status, job and living status (p > 0.05).The older patients had a mean age of about 69 years . The meap = 0.001)  .p = 0.001). To find which distraction intervention was more effective, the Cohen’s d test was used, which showed that visual distraction had a larger affect compared to auditory distraction on the reduction of pain severity after each distraction session as follows: after the first session: d = 2.30; after the second session: d = 2.22; after the third session: d = 2.29   reportedIn our study, the pain level was lower in the visual distraction group with a score of about 1.2 compared with the auditory distraction group. Similarly, Gezginci et al. (2018)  found thIn this study, the combination effects of visual and auditory distractions on the older patients’ pain was not investigated, but their effectiveness has been reported by other studies. For instance, Lee et al. (2004)  showed tThe nature of the interventions made it impossible to blind the older patients. In addition, different psychologic conditions of the older patients undergoing hemodialysis directly could affect their perceptions of distractors during the interventions. Variations in the pain threshold among them and also the impact of cultural factors on the presentation of pain might have influenced the study findings. This study was carried out at one hemodialysis center, which may influence the generalizability of our findings to other contexts and should be considered during the interpretation of findings.The findings of this research support the use of visual and auditory distractions as safe and noninvasive techniques for reliving AVF cannulation pain and improving well-being in the older patients undergoing hemodialysis. While both visual and auditory distractions reduced pain severity in older patients undergoing hemodialysis, visual distraction was more effective. Therefore, nurses working in the hemodialysis unit should be provided with on-the-job training to learn about how to incorporate visual distraction into routine nursing care in order to improve the feeling of safety in older patients undergoing AVF cannulation. Future studies should examine the benefits of visual and auditory distractions and compare them with other non-pharmacologic methods on relieving pain in older patients with various types of chronic diseases.


Pain treatment post orthopaedic care in the elderly is complicated and requires careful follow-up. Current guidelines state all patients prescribed opioids should have a plan for gradual reduction, with the treatment progressively reduced and ended if any pain remains after more than three months. How this works in primary care remains to be explored.The aim was to describe pain treatment and its follow-up in primary care of elderly patients after orthopaedic care.In this descriptive study, medical case histories were collected for patients ≥ 75 years, which were enrolled at two rural primary care units in southern Sweden, and were discharged from orthopaedic care. Pain medication follow-up plans were noted, as well as current pain medication at discharge as well as two, six and twelve weeks later.We included a total of 49 community-dwelling patients with medication aid from nurses in municipality care and nursing home residents, ≥ 75 years, discharged from orthopaedic care. The proportion of patients prescribed paracetamol increased from 28/49 (57%) prior to admission, to 38/44 (82%) after 12 weeks. The proportion of patients prescribed opioids increased from 5/49 (10%) to 18/44 (41%). Primary care pain medication follow-up plans were noted for 16/49 patients (33%).Many patients still used pain medication 12 weeks after discharge, and follow-up plans were quite uncommon, which may reflect upon lacking follow-up of these patients in primary care. Pain treatment in elderly patients is complicated due to age-associated physiologic, pharmacokinetic and pharmacodynamic changes as well as comorbid conditions and the tendency to have polypharmacy –4, notabMild to moderate nociceptive pain in elderly patients should primarily be treated with paracetamol according to international and national recommendations , 4, 7, 8However, since drug related problems are a common cause of hospitalisation in elderly patients , the incBut polypharmacy is also common among elderly patients , especiaPharmacological pain management in the elderly is complicated, even more so for patients with cognitive deficits. Adequate treatment with recommended drugs requires careful follow-up, including pain assessment based on patient self-report or observation of pain behaviours , to miniWe aimed to examine pain treatment and its follow-up in primary care of elderly patients after orthopaedic care, by describing actual treatment at certain points in time from discharge until 3 months later as well as the presence of any follow-up plans regarding this treatment.1.3 million (13%) of the Swedish population lives [The study was conducted at two rural public primary care units in Skåne county in southern Sweden where on lives . This reIn this region, the hospitals and the primary care units have separate electronic medical records. Information transfer from hospital to primary care occurs by a medical case history, as well as a discharge summary which is also given to the patient and nurses in municipality care. There are no current available directives for pain assessment of community-dwelling patients with medication aid from nurses in municipality care or nursing home residents. In Sweden, such patients commonly have many chronic diseases as wells as polypharmacy . NursingPatients were included from March 2014 until October 2017. Inclusion criteria were community-dwelling patients with medication aid from nurses in municipality care and nursing home residents (short-term or permanent), aged 75 years or older, discharged from in-patient orthopaedic care  by examining the electronic medical records and communicating with nurses in municipality care at regular weekly meetings with primary care physicians founded to enable collaboration on shared patients, or by fax . By means of communicating with the nurses and examining medication lists and patient chart entries in the electronic medical records including the medical case histories and discharge summaries, as well as the medication lists in the MDD system, information on current pain medication prior to admission, at discharge as well as two, six and 12 weeks later was obtained. Residence status at discharge as well as whether the patients suffered from dementia was noted, defined as a diagnosis of a major neurocognitive disorder according to p < 0.05.IBM SPSS Statistics 24.0 was used . DescripThe regional ethical committee at Lund University decided there was no need for an ethics review (reference number 2015/171), but gave an advisory opinion stating that no ethical issues regarding the medical record review was seen in this study. An approval for medical record reviewing was obtained from the head of the primary care units.A total of 49 patients were included, of which five patients were lost to follow-up at 12 weeks  from hospital to primary care were noted for 18 out of 49 patients (37%) in total. Pain medication was the main reason for referral in two cases, of which one was received after the patient had revisited the emergency room due to severe pain after discontinued opioid treatment. Nine patients had a hospital discharge plan for gradual reduction of the opioid treatment within 3 weeks (or less) from hospital discharge. A discharge summary with medication report and medication list was noted for 19 out of 49 patients (39%). Patient chart entries regarding pain medication follow-up (i.e. primary care pain medication follow-up plans) were noted in the primary care electronic medical records for 16 out of 49 patients (33%) within 1 week from discharge. A patient chart entry regarding pain, pain medication or adjustment of pain medication (but no plan) was noted for another seven patients.Table Two and 6 weeks after discharge, one patient was prescribed NSAID (ibuprofen or naproxen).p = 0.697). Out of the patients with a primary care pain medication follow-up plan, 5/16 were still opioid users as compared to 13/28 without a plan (p = 0.325).Twelve weeks after discharge, 18/44 patients (41%) were still prescribed opioids for regular and/or as-needed use Fig. . Four oup = 0.001). This was also noted for patients prescribed paracetamol 12 weeks after discharge  as compared to prior to admission  (p = 0.021). Pain medication for all patients over time is shown in Fig. Overall, a greater and statistically significant proportion of patients not lost to follow-up were prescribed opioids 12 weeks after discharge  as compared to prior to admission  (p = 0.049) including regular use  at discharge compared to community-dwelling patients.A significantly lower proportion of patients with dementia were prescribed opioids as-needed compared to patients without dementia Table , also noIn this study on pain treatment in elderly and its follow-up in primary care, many patients still used paracetamol and/or opioids 12 weeks after discharge and follow-up plans for pain medication in primary care were seen for only one third of the patients. At discharge, nursing home residents received less opioids, and patients with dementia less opioids as-needed.The patients in our study were elderly, often suffered from dementia and/or lived in nursing homes. Such patients commonly use MDD, which is associated with fewer drug treatment changes . Hence, At 12 weeks, many patients (82%) in our study still used paracetamol, the first-line analgesic in nociceptive pain , and con. If not routinely carried out, breakthrough pain, function and pain tolerance cannot be evaluated which may also lead to undertreatment.Numerically fewer patients with (5/16) than without (13/28) a primary care follow-up plan used opioids at 12 weeks. Lack of follow-up may contribute to continued treatment without clear indication, with risk of side effects, polypharmacy and unnecessary costs. However, patients without any follow-up or gradual reduction plans also reduced their pain medication use. Whether this was initiated by the patients, the nurses or the GPs without noting it in the medical record is not known. It is possible these patients are actually better monitored by the GPs and the nursing staff than community-dwelling patients without medication aid and treatment therefore terminated when no longer needed. However, regular pain assessments as well as monitoring effect and side effects is a prerequisite for adequate pain treatment in elderlyCognitively impaired elderly hip fracture patients receive significantly less opioids postoperatively , 40. In As for nursing home residents, poorer quality of drug treatment is commonly noted , and manBoth Japan and Sweden have a high life expectancy , and theAs to the influence of genes and ethnicity, one study noted a lower metabolizing capacity of paracetamol for eastern Asians as compared to western Europeans, suggesting that they may be more susceptible to paracetamol induced toxicity . Indeed,In Sweden, prescription pattern data of analgesics during 2006–2015 showed a stable prevalence of opioids while an increase in paracetamol and decrease in NSAID (mainly for the elderly) prescribing was noted . ParacetOur results are well in-line with previous research, but adds the perspective of how it works in primary care, and may initiate a debate on how to improve the follow-up of these patients in primary care, for example with regular pain assessment.However, the role played by the lack of pain medication follow-up plans is not yet entirely clear and should be further examined.Pain management in elderly is a common and challenging task in primary care. The main strength was precisely the primary care perspective; as this is where these patients are mostly cared for.The main weakness was the small study sample, due to difficulties with collecting medical case histories since the research group didn’t personally perform this task. Unfortunately, no better means of data collection was available. However, no subsequent bias was expected or noted. Further description of the possible loss in study population was not possible since all patients discharged from orthopaedic care could not be completely identified. Primary care research is challenging, and lacks experienced research nurses and the like for data collection. Yet, this makes primary care research all the more important, to describe for example how follow-up works in reality.In addition, the results are derived from a limited number of GPs and their actions. Further, the medication information was partially based on reports from nurses in municipality care, assumed to be complete, but not always possible to double-check. Both patients with medication aid and nursing home residents were included, to obtain a study population of elderly patients quite possibly at the highest risk of drug-related problems and in great need of careful follow-up. Also, actual medication use is high for these patients, which strengthens the validity of the data. While forming a mixed sample, it also enables a description of two similar but distinct patient groups. Although the generalisability of our results to a different setting is uncertain, the accordance with previous research suggests a certain degree of credibility.Also, doses of medications were not included, and decreases in daily doses may have been made without discontinuation of the treatment. We also lacked patient pain assessment and hence the degree of pain at each point is not known, which would have been helpful to clarify whether persistent treatment was indicated or a result of poor follow-up. However, this study describes a real situation where potentially risky treatment continues possibly due to lack of regular follow-up including pain assessment .Persistent pain medication was commonly noted, including opioid use at a point in time where it should be gradually reduced and ended, which may reflect poor follow-up of these vulnerable patients.


Given the complexity of pain management in rehabilitation settings, pharmaco-behavioral interventions can capitalize on the self-modulatory process to enhance the effects of a drug-based intervention. Opioid consumption for those in comprehensive inpatient rehabilitation units is high because of the complexity of their injuries. Notably, pain in rehabilitation leads to worsened clinical outcomes because of maladaptive behaviors and poor engagement during therapies. It is critical to developing evidence-based pharmacobehavioral interventions. Based on principles of classical conditioning, conditioning open-label placebo (COLP) is a promising approach for reducing opioid use in comprehensive inpatient rehabilitation, and this technique takes advantage of the possibility of association learning and opioid pharmacology to promote evoked placebo-driven analgesia.In this brief report, we evaluate the feasibility of COLP as a pharmacobehavioral intervention to decrease total opioid consumption in patients with pain hospitalized at Spaulding Rehabilitation Hospital.Inpatients with spinal cord injury and polytrauma (n = 20) with moderate to severe pain were randomized to receive COLP (n = 10) or treatment-as-usual for 6 consecutive days. Opioid utilization was measured by morphine equivalents using the morphine equivalent dose conversion; pain severity was assessed using the numerical visual analog scale.P ≤ 0.001). Pain reduction was also significant for the COLP group (P = 0.005), whereas the treatment-as-usual group demonstrated a trend towards pain reduction (P = 0.05).Conditioning open-label placebo significantly reduced total opioid consumption by the end of the intervention period (This study presents the first data in the use of a pharmacobehavioral intervention that capitalize on the benefits of open-label placebo and classical drug conditioning for opioid dose reduction in a population with moderate to severe pain exposed to intensive inpatient rehabilitation. In a learning phase, the opioid as the unconditioned stimulus is paired with a neutral stimulus—placebo—the neutral stimulus alone becomes a conditioned stimulus, potentially capable of eliciting a conditioned analgesic response after a period of associative learning. Conditioning can be reinforced by adding an olfactory stimulus (smell of a nonfamiliar odor), as the sense of smell is closely aligned with emotional processes, physiologically, and psychologically responses.8 Placebo is a complex psychoneurobiological phenomenon, including the release of endogenous substrates that mediate placebo analgesia.7 This comes from the observation that the opioid antagonist naloxone can efficiently reverse placebo-driven analgesic responses.7 Several theories try to explain this phenomenon, including treatment expectations, anxiety downregulation, cognitive and emotional processes associated with pain perception, and classical conditioning.12 The use of placebos in the clinical arena represents an ethical challenge because deception or concealment is usually thought to be necessary; OLP bypass ethical issues related to deception or concealment.7 Open-label placebo involves the presentation of the placebo to the patient and explaining the purpose and possible benefits of this option. Moreover, OLP has already been successfully demonstrated in a pilot randomized controlled trial (RCT) in patients suffering from pain13 and nonpain conditions.14It has been suggested that combining principles of pharmacological conditioning and open-label (honestly prescribed) placebo (OLP) could lower opioid dosage and still provide the same level of pain relief.A conditioning OLP (COLP) model can be used to optimize pharmacological treatments without deceiving patients. To date, no study has described or evaluated a COLP intervention in the CIR settings or any RCT concerning pain. Here, we hypothesized that a pharmacobehavioral paradigm would result in decreased opioid utilization by eliciting therapeutic opioid dose extension through placebo-induced analgesia.We conducted a pilot RCT in CIR units to explore COLP safety and feasibility. Inpatients from the spinal cord injury and polytrauma units were recruited to participate. Inclusion criteria included (1) hospitalized for intensive rehabilitation and acute pain; (2) spinal cord injury (ASIA A-D); (3) neuropathic and/or nociceptive pain that was moderate to severe ; (4) on current narcotic use for pain control; and (5) narcotic usage of no more than 120 mg of morphine equivalents or 80 mg of short-acting oxycodone.After informed consent, 20 participants in a 6-day trial were randomized to either COLP or treatment-as-usual (TAU) group. All participants were asked whether they had heard of the “placebo effect” or “conditioning” and then investigators preceded to explain these concepts to both groups. Patients randomized to COLP underwent an acquisition phase of 3 consecutive days where oxycodone (as needed - PRN) intake was paired with a placebo capsule and an odorous stimulus (cardamom oil), followed by 3 days of an evocation phase where oxycodone was completely removed on the fourth and sixth day. During these 2 days, the placebo and odorous stimuli were honestly given in case the patient had pain and requested it. The fifth day of intervention was used as reinforcement of the conditioning, with oxycodone reintroduced to the paradigm. Treatment regime and schedule for the COLP group include the short-acting oxycodone—acquisition and reinforcement days—prescribed on a PRN schedule of 5 to 10 mg, 3 to 4 times per day (without exceeding 80 mg of oxycodone/day). The TAU group received analgesic treatment as prescribed by their treating physicians. Treatment included oxycodone at the standard PRN schedule for both groups. Furthermore, patients in both groups had access to analgesic rescue medication if requested.Patients were evaluated using the following tools: (1) morphine equivalent dose conversion (MEDC) factor is used to standardized opioid usage, having as a reference morphine as the main indicator for analgesic potency, and (2) VAS for pain intensity in the past 24 hours (on day 1 and by the end of the sixth day of intervention). All measurements were performed at baseline and after intervention.t test. Analysis of covariance and linear mixed effects model were used to test the main hypothesis while correcting for baseline differences and covariates.Statistical analysis was performed using STATA v.13.1 software . Our analysis followed the intention-to-treat principle by last observation carried forward. The primary outcome was total opioid consumption measured by the MEDC, whereas pain control was evaluated with the VAS as a secondary outcome. Within-group comparison from baseline to postintervention was performed using a paired A total of 20 patients were enrolled and randomized to participate in this trial. One subject was removed from the study because of increased opioid consumption. All participants tolerated the interventions well; there were no direct side effects associated with the placebo capsule, nor the olfactory stimuli. Table t test showed a significant difference in MEDC scores for the COLP group , opioid dosage decreased from 122.5 mg (SD = 114.9) to 56.25 mg (SD = 60.51), representing a drop of 66% in the total opioid consumption  for the COLP group. No significant difference was observed for the TAU group (P ≥ 0.05), opioid use decreased from 65.62 (SD = 53.82) to 61.87 (SD = 58.87), representing a net reduction of 4% by the end of the intervention period.A paired P ≤ 0.001) a predictor of MEDC reduction, whereas group  displayed a marginal effect.Linear mixed model analysis  showed time as , whereas a trend was observed for the TAU group .In the within-group analysis for VAS scores, results showed a significant effect on pain Fig.  for the 16 In this exploratory trial, our results demonstrated the safety and feasibility of a pharmacobehavioral intervention used in a CIR environment. Results were in line with our proposed hypothesis that participants receiving COLP intervention will have lower opioid consumption while maintaining adequate pain control like those in the TAU group. Given the intervention design, a reduction of 30% was expected in the COLP group; surprisingly, the decrease in MEDC scores went well below this threshold by 66%, and this reduction was significant after adjusting for baseline differences. Pain reduction was similar for both groups (1.2-point difference); however, this must be taken with caution because within-group variability is responsible for this difference.Adequate pain management during CIR is imperative. At the forefront of pharmacological treatment for severe pain are analgesic opioids, yet, opioid-based medications now have a negative cloud surrounding them on multiple fronts for both patients and physicians.16Many factors are involved in the expression of a placebo through the therapeutic encounter. Conditioning OLP intervention distinctly takes advantage of patients' treatment expectations and likely nonconscious processes involved with classical conditioning. The addition of an olfactory stimulus reinforced the analgesic learned response due to associative learning. Parallel to the pharmacobehavioral strategy, OLP endorsed an honest approach that facilitated patients' understanding of the “self-regulation” concept, as participants were aware of the “inert” nature of placebo while offering an ethical option for the use of COLP as an intervention. Another decisive factor may have been the interaction between patients and clinicians—particularly the nursing team—because they closely monitored the patient's responses to COLP (to insure against poor pain control), highlighting the role of enriched care for patients with severe medical conditions.15 Given the complexity of pain management in CIR, there is a need to explore innovative pharmacobehavioral interventions that can take advantage of the self-modulatory process to enhance the effects of a drug-based intervention. Investigations to determine physiological markers of response are further needed. The sample size is the main limitation of this trial; although we did not look for efficacy because of the exploratory nature of the design, our results provide directions for further investigations. Conditioning open-label placebo showed how pharmacotherapy effects can be augmented by associative conditioning enabling opioid “dose extension” through opioid dose reduction. In the future, we intend to perform a longer trial and try to separate the impact of conditioning and OLP involved in this treatment.There is pressure for pain medicine to shift away from reliance on opioids and ineffective procedures toward comprehensive pain management that includes evidence-based nonpharmacologic options.The authors have no conflicts of interest to declare.This research was supported by funding from the Spaulding Research Catalyst award and the Ellen R. and Melvin J. Gordon Center for the Cure and Treatment of Paralysis. L. Morales-Quezada was funded by the Institutional National Research Service Award from the National Center for Complementary and Integrative Health (NCCIH grant number T32AT000051) and the Foundation for the Science of the Therapeutic Encounter (F-STE).