Background: Strong opioids are mainly utilized to attenuate pain in cancer patients. Adherence to analgesic drugs significantly promotes adequate pain management and improves quality of life.We aimed to identify the factors influencing non-adherence to strong opioids in cancer patients.Methods: A descriptive, cross-sectional, two-phased, mixed methods design was conducted prospectively to evaluate a cohort of 101 cancer patients who are currently prescribed strong opioids from a pain clinic in Thailand between January and March 2018.Participants were asked to complete a questionnaire that included the following sections: general characteristics; the Medication Taking Behavior in Thai (MTB-Thai) for assessing adherence to medications; and factors influencing nonadherence, which were analyzed using multivariate logistic regression. In addition, face-to-face in depth interviews were conducted with patients showing non-adherence to strong opioids (MTB-Thai score ≤21) and analyzed using thematic content analysis. Results: Of 101 cancer pain patients that completed the questionnaire, 39.6% showed non-adherence to strong opioids. Illness understanding (P=0.047) and the use of more than three types of pain medication (P=0.032) were significant factors influencing non-adherence. Qualitative analysis indicated that fear of long-term outcomes, opioid side effects, ineffective pain control, attempts to make the regimen more acceptable, poor understanding, and non-acceptance of disease related to non-adherence.Conclusion: Non-adherence to opioids for cancer patients is a common problem. Awareness of patient factors, medication-related factors, and illness-related factors will provide the knowledge and adequate advice that may enhance adherence to medications. In Thailand, an average of 170,000 people were newly diagnosed with cancer in 2018, according to the World Health Organization report2. More than one-third of cancer patients experienced moderate or severe pain3. Improper pain management can be caused by a multitude of factors, including the clinicians’ attitude, patients’ perception, caregiver’s perspective, and the availability or accessibility of analgesic drugs9. Significantly, poor adherence to the analgesic regimen can contribute to ineffective cancer pain management12. Also, it can lead to a substantial worsening of the disease, death, and increased health care costs13.Cancer is the one of four non-communicable diseases that makes up the majority of global deaths14. Previous research on the causes of non-adherence has identified various factors, such as illness, drugs, medical personnel, patient characteristics, and socioeconomic factors15. Notably, poor compliance is associated with young age, smoking, fear of drug dependence and side effects, the experience of adverse events, misunderstanding of prescriber instructions, poor beliefs and perceptions, poor family support, and non-acceptance of illness20. However, no study in Thailand has explored the issue of opioid non-adherence in patient-related factors, which is one of the most significant barriers and is a severe problem that obstructs pain management goals. Furthermore, non-adherence to opioids remains a significant health problem, and more high-quality studies are needed to assess these aspects. The study aims to explore the factors influencing opioids non-adherence in cancer patients by using mixed-methods design.Strong opioids are the mainstay for treatment of cancer pain. The reported incidence of poor opioid adherence is 50–70% of patients with advanced cancerThe present study was a descriptive, cross-sectional, two-phased mixed methods study using both quantitative and qualitative approaches. The study was conducted between January and March 2018This study was approved by the Ethics Committee (Chairman Assistant Professor Dr. Chusak Okascharoen) of Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand . Participants were informed about the study and provided written informed consent to participate in both the questionnaire and the interviews. All data were confidential.21. The calculation formula of Taro Yamane is presented as: n = N/1 + N (e)2The sample size for the study was determined using Taro Yamane sample size formula with 95% confidence levelwhere: n = sample size required, N = number of people in the population.In this study cancer pain patients attending a pain clinic at Ramathibodi Hospital, Bangkok, Thailand were the sample population and numbered 134 in the last three months between January and March 2018; therefore, e = allowable error (%)-0.05. A minimum of 101 cancer pain patients who used strong opioids  by oral and transdermal routes of administration were required to meet the sample size. Participants who had the follow-up appointment schedule were selected using simple random sampling by computer generated random list. They were approached during a routine follow up at pain clinic.The inclusion criteria were patients aged 18 years or older, diagnosed with cancer pain, strong opioid analgesics for cancer pain prescribed for more than one week for around-the-clock use or as needed, and ability to communicate well in Thai. Exclusion criteria were patients who declined to participate, and who had known or suspected psychotic disease.23. Other factors associated with non-adherence to strong opioids, including patient factors  were assessed using a copyrighted Thai version of the self-report Belief about Medication Questionnaire [Thai-BMQ])25. For the questions about knowledge assessment of strong opioid analgesics were created by pain specialist. Socioeconomic factors , medical personnel factors , medication-related factors  and illness-related factors were also assessed. Both MTB-Thai and Thai-BMQ were used in the study with permission of the originators of the questionnaires and completely validated. The full questionnaire used in this study was approved by three pain specialists. Content validity was determined by obtaining the item objective congruence (IOC) value for each questionnaire  ranged from 0.80 to 0.92. All were >0.5, indicating good content validity. Cronbach’s alpha coefficient of the questionnaire ranged from 0.702 to 0.788; a score of >0.7 indicates acceptable internal consistency27. The questionnaire was not modified after the pilot with 10 patients. A copy of the questionnaire can be found in theExtended data27.All participants filled out the questionnaire by themselves and participated in the interviews at the hospital. The questionnaire assessed demographic characteristics, pain severity  with therapeutic outcomes , and medication adherence using the Medication Taking Behavior in Thai (MTB-Thai) measure 27. These questions were asked in a face-to-face qualitative in-depth interviews by the second (MA) and the fourth author (RM) that were conducted until data saturation was reached. The interviews were audio-recorded with the patients’ permission, and the interviewers also took field notes.Open-ended interview questions were included at the end of the questionnaire for patients who had a MTB-Thai score ≤21, in order to provide further commentary and suggest other factors that may influence non-adherence to strong opioids. The open-ended of the interview included four questions related to the experienced of using strong opioids for pain control and outcomes, patients’ concern, and healthcare service systemSPSS for Windows version 18.0  was used for quantitative data analysis. Descriptive statistics, such as frequencies, percentages, means, and standard deviations, were used to analyze demographic data. Chi-square test, relative risk, 95% confidence intervals (CI), and p-values were used to measure the association between factors and strong opioid analgesic non-adherence. Multiple logistic regression was performed to identify risk factors for opioid non-adherence and to calculate adjusted risk ratios. P-values less than 0.05 were considered statistically significant.Interview data (transcribed verbatim from recordings) and the interviewers’ memos were subject to thematic content analysis using ATLAS.ti software version 8.0. Using five stages of data analysis in the framework approach included: 1) familiarization or immersion in the raw data to list key ideas and recurrent themes, 2) identifying a thematic framework , 3) indexing or applying the thematic framework or index systematically to all the data in textual form by annotating the transcripts with numerical codes, 4) charting or rearranging the data according to the appropriate part of the thematic framework to which they relate, and forming charts, and 5) mapping and interpretation by using the charts to define concepts, map the range and nature of phenomena. All 101 participants completed the questionnaire . Most paStatistically significant differences between the adherence and non-adherence groups were found in the general-overuse dimension of the Thai-BMQ (P = 0.047), illness understanding (P = 0.028), and use of more than three types of pain medication (P = 0.035) .The multivariate analysis showed that two variables had significant associations with opioid non-adherence: illness understanding (P = 0.047) and use of more than three types of pain medication (P = 0.032). The illness understanding and acceptance part of the questionnaire contained five statements. Most participants agreed with either “I understand my illness, and I think I received the best treatment” or “I understand my illness, but I think I could have received better treatment.” Patients who chose the former response were less likely to show non-adherence than those who chose the latter answer . Participants prescribed more than three types of analgesics had a 3.04 times higher risk of medication non-adherence than participants prescribed three or fewer types of medication  .Saturated data, in total 10 individual in-depth interviews with patients who had MTB-Thai score ≤21 were conducted, which lasted around 30 to 45 minutes. Five themes related to opioid non-adherence emerged from the data: fear of long-term outcomes, desirable or undesirable opioid side effects, ineffective pain control, attempts to make the regimen more acceptable, and poor understanding and non-acceptance of the disease. Analytic results of the contextual factors associated with non-adherence to opioids in cancer patients are presented inPatient factorsTheme 1: Fear of long-term opioid adverse eventsAlmost half of the patients were concerned about opioid addiction. Some chose to be in pain to minimize the chance of addiction. As two patients remarked:          “I could get addicted to the medication, so I don’t want to take morphine syrup more than once a day.”          “I feel uncomfortable taking morphine in front of people. They look at me like I am addicted to drugs.”Many patients were afraid of liver or kidney damage after long-term opioid use and combined with other pain medications, despite their physicians confirming the safety of their opioid dosage. As some patients mentioned:          “Morphine could reduce my pain but if I take as much as I need, I will suffer from liver or kidney disease in the future.”          “I took lots of medication. I think my liver has had to work too hard, so I wait until I had severe pain, I will take morphine.”          “These drugs can relief the pain, but I wondered if just one or two drugs could control everything. I think that taking four types of drugs every day will damage my health.”Medication-related factorsTheme 1: Desirable or undesirable opioid side effectsMany patients reported opioid side effects. Some found that the side effects were unbearable and affected their quality of life. Commonly reported severe constipation, upset stomach, and drowsiness. As some patients said:          “I am in pain but I chose to use as low a dose of morphine as I could because it made me constipated.”          “Severe nausea made me afraid to use morphine. Throwing up was much worse than living with this pain.”          “I always had to take a nap after taking morphine. So I could only take it before bedtime otherwise I might sleep all day.”Notably, some participants found specific side effects beneficial, whereas others found them problematic. As one patient said:          “The rescue drug makes me sleep well at night. I take it every night even if the pain does not bother me much.”Theme 2: Ineffective pain control Some patients do not adhere to medical regimens because they find pain medication ineffective. Some participants reported not taking opioids because they did not have the intended effect. As one patient remarked:          “I suffered from pain, but the drug did not make me feel as good as I expected. So there was no reason for taking it.” Some patients increased their basal opioid doses because their pain had worsened and dared not to call to consult the doctor about ineffective pain control. As one patient remarked:          “I did not know what to do with my pain anymore. I felt so hopeless. I took morphine syrup every hour. The effect was too short-lived, so I tried to take more morphine tablets than the doctor had prescribed, but I ended up feeling sleepier all day.”Theme 3: Attempts to make the regimen more acceptableSome patients applied their medication regimen to suit their lifestyle and drug reactions. Some reduced the medication frequency, as they felt uncomfortable taking medicine at midday. Others changed the regimen from around the clock to after meals, because it was easier to remember. Some took all their drugs at bedtime rather than in the morning because of the sedative effect. As some patients said:          “I go to work every day. It’s not easy to bring the drugs with me, so I changed the schedule from a three times daily regimen to a two times daily regimen. I think this work for me.”          “I take the morphine after meals. It is easier to remember. I used to forget to take the pills at 2 pm, which made the pain worse in the evening.”          “I felt sleepy after I took the pills, so I took it all at night before bedtime. This meant that the pain wasn’t well controlled, but that’s better than feeling drowsy all day.”Illness-related factorsTheme 1: Poor understanding and non-acceptance of the diseaseIf doctors can improve patients’ understanding and acceptance of illness, then more collaborative treatment decisions can be made. If patients insist on seeking complete pain relief or a complete cure and are reluctant to adopt modified life goals and activities, it is difficult to set realistic treatment goals. Acceptance-based pain management may be helpful for cancer patients. Many patients reduced or discontinued opioids by themselves when their pain was decreasing. As two patients said:          “I took the pills everyday as advised and they controlled the pain well. I wondered if I could stop taking these drugs, so I tried to stop and the pain came back. Are these drugs helping me with the disease? Or I should try something else?”          “After taking the drug, I feel better, I stopped taking it on some day. I think the disease is getting better.”28. Our data indicate that only three out of these five factors were significantly associated with non-adherence: patient factors, medication-related factors, and illness-related factors.The main purpose of this mixed-methods study design was to explore the factors influencing non-adherence to strong opioids in cancer pain patients. Most research has studied the clinical factors associated with adherence to opioids for cancer pain and has not focused the medical non-adherence factor alone. Investigation of non-adherence to opioids in cancer patients is a pro-active useful model for correcting beliefs, attitudes and behavior. This study asked participants about characteristics related to themselves, family and social support, doctor-patient relationships, medication-related factors, and illness-related factors. The incidence of non-adherence of our study was 39.6%, similar to previous study33. This was even though most of the patients from this study had a higher education and good knowledge of strong opioids. They may also be concerns about the adverse effects of opioids. Similarly another study found that some patients who were educated about the side effects of medication showed increased concerns about the risk of addiction35.In the quantitative data, patients’ knowledge of strong opioid analgesics and their beliefs about medication were not significantly related to non-adherence. However, the interviews revealed a concern about adverse effects, side effects, opioid addiction and multiple organ failure from long-term usage, as reported in previous work36. Healthcare providers should reassure patients by emphasizing the benefits rather than the risks of opioids, and should identify patients’ concerns. Additionally, involvement of patients in the treatment decision-making process may help to reduce fear and facilitate adherence37.Generally, cancer patients require long-term use of strong opioids. Physicians should educate patients during treatment about the prevention of adverse effects. Although patient education is a key component of adherence, more education may make patients anxious and fearful about opioid adverse effects. Patient beliefs and attitudes regarding the effectiveness of the treatment, and lack of motivation, also affects medication adherence38 found an association between medical adherence and family and social support: adherence was 1.74 times higher in patients from cohesive families and 1.53 times lower in patients from families in conflict. The present findings did not show a correlation between adherence and family support. More than 90% of patients in both the adherence and non-adherence groups confirmed that they received the best care from their families when needed. This may be because Thai people live in large families and therefore find it relatively easy to obtain assistance when needed.A previous study39 found a correlation; patients who believed that doctors treat patients as equals, who felt that doctors discuss treatments with patients before making decisions, and who could choose their doctor were more likely to adhere to recommendations.Almost all patients expressed high satisfaction and confidence in the pain clinic services and staff. Therefore, the doctor-patient relationship was not significantly associated with non-adherence. One previous study41. Our quantitative analysis showed that use of more than three types of drugs was associated with a 3 times higher risk of non-adherence than use of less than three types. Furthermore, the qualitative analysis identified three themes related to medication-related non-adherence factors. Similar to a previous study40, we found that some patients reduced their opioid dose to avoid unbearable side effects, such as constipation, nausea, vomiting, dyspepsia, or drowsiness. Despite having poor pain control, they could not take the opioid dose prescribed because of the side effects. Most said that their pain was much more bearable than the side effects. Some did not inform their doctor about their pain owing to limited time, being considerate or shame. Moreover, some patients used opioids for the wrong reasons; for example, taking opioids at night to help them sleep even when they had no pain.Both the quantitative and qualitative data revealed many medication-related reasons for non-adherence, which reflected previous study findings41, we found that ineffective pain control was a key reason why some patients refused to take prescribed medication. Some patients increased the prescribed opioid dose for maximal pain relief. Some obtained opioids from many different hospitals to control the pain without discussing this with their doctor. Patients reported many reasons for non-adherence. Some felt that their doctor had insufficient time to listen to their problems. Others were afraid that the doctor would abandon them because they did not use the drugs as prescribed.In accordance with previous findings40. Patients changed the drug schedule to suit their lifestyle. Some patients reduced the dose frequency as they were not comfortable taking drugs at certain times of the day. Some changed the interval from around the clock to after meals, as it was easier to remember. Some patients took all their medications at bedtime rather than in the morning because of the sedative effects.One of the medication-related factors we identified was the attempt to make the drug regimen more acceptable; this has also been reported in previous work43 and that acceptance-based pain management may be helpful for cancer patients44. The present quantitative and qualitative data show that patients with poor illness understanding and non-acceptance of the disease show medication non-adherence. In our study, patients misunderstood their situation and believed that they could be fully cured and become pain free. Some patients believed that there were better treatment options than the treatment they had received. The results suggest that enhancing the acceptance of pain and cancer may be a clinically relevant management goal.Previous studies of patients with chronic nonmalignant pain indicate that illness acceptance predicts increased psychological, social, and physical functioningAlthough many factors were not statistically significant in the quantitative study, such as the patient’s belief about opioid side effects or adverse effects; however, more than three types of pain medication may be the critical factor of non-adherence that might raise their concern about long term adverse effects as opioid addiction or multiple organs failure. Also, taking multiple drugs may be a factor that causes patients to adjust their medication as appropriate, which causes inadequate pain relief. From the in-depth interviews, it was clear that concerns about medication side effects, fear of adverse events and poor pain control were barriers for opioid use in cancer pain management.Mainly, the various opioids are very different in bioavailability, metabolism, and response between individual patients. Appropriate opioid use must be selected for each cancer patient, and the dose must be individually titrated. Effective and safe titration of opioids has a significant impact on patient comfort. Obviously, several complex factors affect opioids non-adherence in cancer patients. Therefore, we recommend the following strategies to improve adherence to strong opioid medication for cancer pain.1. Understanding patients’ reasons for non-adherence to opioids could help doctors to identify how these patients may present clinically, address patients’ concerns about opioids, and encourage doctors to offer patients alternatives to opioid treatment.2. Reviewing the number of medications because of drug interactions can be managed by reviewing the patient’s medication profile for duplicate or unnecessary medications.3. 45. For example, discussing a patient’s concerns about the risk of addiction may help the patient and doctor to set up plans to monitor misuse or identify less risky or more acceptable alternative pain management strategies.Good patient-doctor communication may reduce anxiety, and also improves pain controlWe only measured non-adherence to strong opioid analgesic medicine. The patients might have been taking other medicines for pain control prescribed simultaneously. As these medicines could have affected pain control, they might have confounded the present results.Almost half of cancer pain patients prescribed opioids showed non-adherence to the medical regimen. Three factors were significantly associated with medication non-adherence: patient factors (fear of long-term outcomes), medication-related factors , and illness-related factors (poor illness understanding and non-acceptance of the disease).rattaphol_nu@hotmail.com, who will facilitate this process.The recordings and transcription of interviews are not openly available in order to conserve the confidential information of participants. All document files were eradicated immediately following data analysis. Themes and quotes from the data analysis are available in Thai. This data can be obtained by application to the Ethical Committee of Faculty of Medicine Ramathibodi Hospital. To apply, please contact the corresponding author athttps://doi.org/10.6084/m9.figshare.13336691.v246.Figshare: Data of factors influencing non-adherence to opioids in cancer patients.xls.,https://doi.org/10.6084/m9.figshare.13336754.v126.Figshare: Questionnaire and open ended questions in English.doc.,https://doi.org/10.6084/m9.figshare.13336766.v227.Figshare: Thai version of the questionnaire and open ended questions.docx.,https://doi.org/10.6084/m9.figshare.13336778.v147.Figshare: STROBE checklist for ‘Factors influencing non-adherence to opioids in cancer patients: a mixed-methods cross-sectional study’,https://doi.org/10.6084/m9.figshare.13336793.v148.Figshare: COREQ checklist for ‘Factors influencing non-adherence to opioids in cancer patients: a mixed-methods cross-sectional study’,Creative Commons Attribution 4.0 International license (CC-BY 4.0).Data are available under the terms of the Thank you for the opportunity to review the revised article. I have no further comments for this paper.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?PartlyIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?PartlyReviewer Expertise:Clinical Pharmacy, medication adherenceI confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you for the opportunity to review this article. It is an interesting read. Non-adherence to opioids for cancer pain is well known in the literature. However, the mixed method employed in this study further explore reasons behind non-adherence specific to the Thai population.English editing is required for this article.“A mixed-methods study is required to study the effects of compliance in enhancing the impact of treatment” – this sentence is unclear. Was this investigated in this study?Introduction: MethodPlease explain simple random sampling used in this study.Please state if Medication Taking Behavior in Thai (MTB-Thai) and Belief about Medication Questionnaire (Thai-BMQ) are validated questionnaires.How were these questionnaires scored? E.g. How did you classify patients as non-adherent based on MTB-Thai? Similarly, for the other questionnaires. “item objective congruence (IOC) value for each questionnaire…ranged from 0.80 to 0.92. All were <0.5, indicating good content validity.” - Please check if this statement is correct.Cite references used for values indicating good content validity and acceptable internal consistency as stated in the method section.ResultsWould the result be different if number of painkillers is analysed as a continuous variable rather than categorical (< 3 and ≥ 3)? (Table 2).Under Table 2, for Patient Factors, Knowledge score (0-10), which questionnaire was used to assess this? Please elaborate under methods section.Why only 10 patients interviewed for qualitative analysis? What were the questions asked in the interviews (can explain this under method section: in depth interviews).“The drug makes me sleep well at night. I take it every night even if the pain does not bother me much”) non-adherent to the pain killer? This seems strange as patient would take the medication if it is producing the desired effects.Was the patient who had a desirable opioid effect  other adjuvants analgesics in cancer pain treatment, for example, anticonvulsants, antidepressants, Non-steroidal Anti-inflammatory drugs, or acetaminophen. In the section, the patient factors in the part of knowledge score of the questionnaire. A pain specialist created the knowledge assessment of strong opioid analgesics that were completely mentioned in the method section.In the part of face-to-face in-depth interviews by the co-authors. The interviews were audio-recorded, and the interviewers also took field notes. The study was conducted until data saturation was reached that approved by primary and secondary authors.A result of medication-related factors, the patients mentioned using the rescue opioids for sleep well rather than for analgesic effects.Discussion:The authors elaborate on the study results so that it is clear in the description of the second theme (ineffective pain control). Some patients increased their basal opioid doses because their pain had worsened and dared not to call to consult the doctor about ineffective pain control by many reasons. Among the interviews, some patients expressed thoughtfulness.In our study, the patients mentioned as following the results in theme 1: Poor understanding and non-acceptance of the disease.In table 3. Univariate and multivariate logistic regression results. In our study, more than three types of pain medication had significant associations with opioid non-adherence (P = 0.032), which related to the quantitative study that the patients mentioned about adverse effects and multiple organ failure if using medications in the long-term. This study used a mixed method of a survey and an in-depth interview to evaluate factors affecting opioid non-adherence in cancer patients. The questionnaire survey was to identify adherence and non-adherence patients, followed by an in-depth interview in patients with non-adherence until data were saturated. Using the mixed method makes the study more informative and attractive. The flow of the study was clearly presented.  Adequate pain management in cancer patients is mandatory. It is useful to know which factors lead to poor pain control. The authors have found factors which can be classified into patient factors, medication-related factors and illness-related factors. Knowing the contributing factors for inadequate cancer pain management can lead to strategic planning to modify these factors resulting in better pain relief.Is the work clearly and accurately presented and does it cite the current literature?YesIf applicable, is the statistical analysis and its interpretation appropriate?YesAre all the source data underlying the results available to ensure full reproducibility?YesIs the study design appropriate and is the work technically sound?YesAre the conclusions drawn adequately supported by the results?YesAre sufficient details of methods and analysis provided to allow replication by others?YesReviewer Expertise:Pain management including acute, cancer and chronic non-cancer pain.I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. Thank you very much.


However postoperative pain remains problematic. No strategy to reduce phrenic nerve irritation, including heating or humidifying the insufflating gas, alternatives to CO100 women undergoing laparoscopic surgery were randomly allocated, having either 40ml of 0.25% levobupivacaine or 40ml 0.9% sodium chloride solution administered into the peritoneal cavity following surgery. The patients and the main researcher were blinded. All women received standardised anaesthetic and laparoscopic technique, and postoperative pain control including nursing position and nature of analgesia. Postoperative pain was assessed 3 hours, 8 hours, day 1 and day 4/5 postoperatively.100 patients were recruited undergoing surgery for benign causes aged 19-73(mean 40.3±13). There was no difference between the groups for age(p=0.64) or length of operation(p=0.56). There were no adverse events related to use of intraperitoneal instillation. There was a significant reduction in shoulder-tip pain scores in the levobupivacaine group at 3 hours(p=0.04). Furthermore, there was a significant reduction in wound-pain scores in the levobupivacaine group at 8hrs(p=0.04) and at day 4(p=0.04). No difference was found in pelvic pain between the two groups. No significant difference was found in the use of post-operative analgesia.Intraperitoneal instillation of 40ml of levobupivacaine has some benefit in reducing postoperative pain and need for analgesia in the initial hours following gynaecological surgery. However, further well-designed randomised control trials are required to decide the optimum route and concentration of administering local anaesthetic. Laparoscopic surgery has transformed modern gynaecological surgery. Its many advantages include shorter hospital stay, reduced blood loss, smaller incisions, and overall reduced morbidity for the patient . However2. Shoulder tip pain arises due to phrenic nerve irritation, again as a result of CO2 trapped under the diaphragm  narcotics are effective medications but increase morbidity and delay discharge . Non-nar2 to peritoneal fluid might lead to acidic irritation of the peritoneum, however, NO2 did not reduce pain in a randomised controlled trial . The trial was registered on the European Union Clinical Trials Register (EudraCT No. 2009011207-23). The women had an American Society of Anesthesiologists (ASA) anaesthesia risk classification status 1-2 and were scheduled to have laparoscopic surgery under the same gynaecological surgeon. Exclusion criteria were women with a BMI>35 due to increased surgical risks and complexity, those who weighed less than 50kg due to risk of local anaesthetic toxicity, those with an ASA >2, or those with a known previous adverse reaction or any contraindication to levobupivacaine.The patients were informed about the numerical pain rating scale (NRS) with 0 being no pain and 10 being the worst possible pain. This allowed answers to be conveyed over the telephone following discharge. A score would be requested for pain for the abdominal wound sites, pelvis, and shoulder tip.The patients were randomly assigned into two groups by computer randomisation. Group 1 (n =50) would receive 40 ml of intraperitoneal 0.25% levobupivacaine, and Group 2 (n = 50) would receive 40ml of intraperitoneal sodium chloride 0.9%. Due to the lack of conformity in the literature, the dose of levobupivacaine was decided due to the clinical experience of the team and the maximum non-toxic dose of the minimum weight patient included in the study. The study was double blinded; the patients, surgical and anaesthetic teams were blinded to the medication used. The packets containing either 0.9% saline or 0.25% levobupivacaine solutions were prepared within pharmacy by computer randomisation code, blinded, and opened by the anaesthetists after induction of anaesthesia.2 +N2O and Sevoflurane. Standard ventilator settings were: PCV-VG mode, Vt of 500mls, frequency 12/min, inspiratory to expiratory ratio of 50% and maximum inspiratory pressures were limited to 30cm H2O. The aim was to achieve mild hypocapnia at 4.5-4.8% end expiratory CO2 and haemoglobin saturation with O2 of 96-98%. Prior to the insertion of umbilical port every patient received 10 mg of Morphine intravenously (iv). All patients underwent their planned gynaecological surgery in a Lloyd Davis position with the table in a 20 degree Trendelenburg tilt.After intravenous cannulation, all patients received intravenous antiemetic prophylaxis consisting of Atropine 400-600ug, Metoclopramide 10mg, Ondansetron 8mg and Dexamethasone 6.6mg followed by 100ug of Fentanyl. Following pre- oxygenation, general anaesthesia was induced with 2-3 mg/kg of Propofol and 0.5mg/kg of Atracurium. All patients were mechanically ventilated with 50% mixture of OLaparoscopic technique was standardised as far as practicable. The same lead surgeon performed a closed umbilical laparoscopic entry with a Verres needle, initial 20mmHg pressures to facilitate a 10mm umbilical and two 5mm lateral port insertion followed by operating pressure of 12mmHg.2 values and the total requirement of anaesthesia was recorded at 5-minute intervals. Following completion of the surgery Group I was instilled with 40ml of 0.25% levobupivacaine and Group II 40ml of normal saline via the lateral port and directed under vision towards the pelvis. The CO2 was then expelled from the abdomen through the umbilical trochar and the tilt was corrected. The incision sites were closed with a 2/o caprosyn suture.During surgery, heart rate, non-invasive arterial blood pressure, oxygen saturations, end-tidal COOnce the patient was taken into the postoperative recovery area this was defined as hour 0, with the first pain score being taken 3 hours following this time. Pain scores were assessed via questionnaire at 3 hours, 8 hours, 24 hours, and 96-120 hours post- operatively. Routine safety monitoring took place in the recovery area, including blood pressure, pulse and pulse oximetry, urine output, vaginal loss, and the patients were all nursed in the same position. Monitoring continued postoperatively at standard intervals until discharge. Standard postoperative pain control had been agreed, with a record of all postoperative analgesia administered whilst in the hospital and taken after discharge until the final pain score at day 4/5. The patients were asked to give a pain score for the pelvis, shoulder tip and wound site at 3, 8, 24 hours and day 4/5 following the surgery.Using the data from a previous study by Sharma et al.  a power Descriptive data is presented as mean ± SD for continuous data and n (%) for categorical data. T-tests were used to compare continuous data, Mann Whitney for ordinal data (e.g. pain scores) and Chi- square tests for categorical data. For the primary outcome measure (NRS), Mann Whitney tests were used to compare pain scores between groups at each time point. For the primary endpoint (8 hours), ANCOVA was used to compare pain scores between groups, whilst adjusting for baseline scores. In addition, potentially confounding variables were included (age and operative time).100 patients were included in the study; 50 received 40mls intraperitoneal 0.9% saline and 50 received 40mls 0.25% intraperitoneal levobupivacaine. Patients were aged 19-73 (mean 40.3 ± 13). There was no significant difference between the groups for either age (MW p=0.64) or operative time (MW p=0.56) . All patThere was a significant difference in the wound pain scores, with the 0.25% levobupivacaine group having lower pain scores at 8hrs (MW: p=0.04) and at day 4 (MW: p=0.04), compared to 0.9% sodium chloride group , althougThere was a significant difference in shoulder tip pain scores, with the 0.25% levobupivacaine group having lower pain scores compared to the 0.9% saline group at 3 hours (MW p=0.04), although significance was lost at 8hrs (MW p=0.06) and not regained.No significant difference was found for pelvic pain at any timepoint. An ANCOVA test was used to compare reported pain at 8 hours when adjusted for the pain score at 3 hours thereby adjusting for baseline pain. No significant difference between the groups was seen for pelvic (MW p=0.20), shoulder tip (MW p=0.19) or wound pain (MW p=0.18). Similarly, no difference between groups was seen when adjusted for age or length of operation.The requirement for post-operative analgesia was also assessed . There wA subgroup analysis was performed on patients who had undergone laparoscopy for treatment of endometriosis (n=50), 25 in the 0.9% saline group and 25 in the 0.25% levobupivacaine group, all of whom had stage 3 or 4 disease. There was a significant reduction in wound pain at 3 hours (MW p=0.015), 8 hours (MW p=0.016) and 4 days (MW p=0.013) as well as shoulder pain at 3 hours (MW p=0.04) and 4 days (MW p=0.04) in the 0.25% levobupivacaine group.2 . This is likely due to the residual pelvic pain which was not altered by the intervention. However, the need for analgesia is a complex interaction of experienced pain, patient expectations, and nursing protocols. We undertook several other measures to reduce the post-operative need for analgesia including the use of intra-operative fentanyl and careful expulsion of residual COa et al.  demonstra et al.  reportedAndrews et al.  comparedAn RCT on women undergoing laparoscopy for gynaecology procedures by Butala et al.  instilleThere was no difference between the groups for adverse events (p>0.1). There were 3 adverse events in total. One in the 0.25% levobupivacaine group, where the patient reported pain secondary to pre-existing irritable bowel syndrome. One patient experienced itching at the cannulation site following administration of IV morphine, and one patient aspirated under anaesthesia  requiring a prolonged hospital admission. There were no significant surgical intra-operative complications.A recent Cochrane review has assessed the use of wound infiltration of local anaesthetic in post-operative pain following laparoscopic cholecystectomy. They conclude that whilst serious adverse events are rare, the quality of evidence for reduction of pain is low and the clinical importance is small . FurtherIn conclusion, intraperitoneal instillation of 40ml of 0.25% levobupivacaine has some benefit in reducing postoperative pain in the initial few hours following gynaecological surgery. It is a safe and easy to perform technique with, no additional need for equipment, time or training, and may have some reduction in need for analgesia.


In this study we analyze new clinical data in the use of spinal cord stimulation (SCS) for the treatment of pain and motor symptoms in patients with Parkinson’s Disease (PD), as both a singular bioelectric therapy and as a salvage therapy after deep brain stimulation (DBS).Fifteen patients were recruited and had percutaneous electrodes implanted at the level of the thoracic or cervical spine. Participants were set to one of three stimulation modes: continuous tonic stimulation, continuous Burst stimulation , or cycle mode  with Burst . Patients completed the Visual Analogue Scale (VAS), Unified Parkinson’s Disease Rating Scale, Self-Rating Depression Scale, Hamilton Depression Rating Scale, Profile of Mood State, 10-meter walking test, and the Timed Up and Go (TUG).All patients experienced significant improvement in VAS scores with a mean reduction of 59% across all patients. Patients who chose the cycling burst stimulation parameter had an average 67% reduction in VAS scores, as compared to the continuous burst parameter group, which had an average 48% reduction in VAS scores. Seventy-three percent of patients experienced improvement in the 10-meter walk, with an average improvement of 12%. Sixty-four percent of patients experienced clinically relevant improvements in the TUG, with an average improvement of 21%.This study points to the potential utility of SCS to address both pain and certain aspects of motor symptoms in PD patients who have and have not received DBS therapy. Parkinson’s disease (PD) is a progressive multi-system, neurodegenerative disease that leads to both motor and non-motor symptoms  technology. Spinal cord stimulation of the dorsal columns within the epidural space has already been shown to be beneficial in a multitude of pain conditions Jeon, . SCS hasIn this non-randomized study, a total of 15 PD patients were recruited through a convenience sampling method, whose pain was refractory to medical therapy and other conservative treatments. The etiology of pain was determined by history and neurological physical findings, imaging diagnosis using MRI and CT, and responsiveness to nerve block and medications. The study was approved by the Institutional Review Boards at each respective center. The PI and sub-investigators referred subjects to the study from their own practices, if the patients were eligible to be implanted with the SCS system and were interested in participation. Patients were included in the study if they had chronic pain of predominantly neuropathic origin that was refractory to conventional treatments such as analgesic drugs and nerve blocks. In addition, patients were eligible if their pain had not improved even with adequate dopaminergic drug administration and adjustment of DBS parameters (if the patients had previously received DBS). Most patients had fluctuating pain in conjunction with motor fluctuations. For example, the patients’ pain increased when they were off dopaminergic drugs and/or when DBS was turned off. Overall, the causes of pain in the patients enrolled in this study were as follows: 5 cases after lumbar spine surgery, 4 cases of radicular pain due to compression fractures , 1 case of radicular pain due to severe spinal scoliosis, 3 cases of postural abnormalities (in this group pain occurred by standing for a long time with scoliosis and bent posture), and 2 cases with unknown etiology  and an average PD duration of 17 years (SD 8.7) , the revised Unified Parkinson’s Disease Rating Scale (MDS-UPRS), Self-Rating Depression Scale (SDS), Hamilton Depression Rating Scale (HAMD), Profile of Mood State (POMS-II), 10 M (10-meter) walking test, and a Timed Up and Go (TUG) at each clinic visit. Each participant had a family member or close friend present during clinic visits to help answer questionnaires.Mean and standard deviations were calculated for two separate groups, those who had DBS prior to entering the study, and those that did not. Paired two-tailed t-tests were calculated comparing pre-intervention means and post-intervention means within each group Table . As a sep < 0.005) (Table p < 0.0007), and for those who did receive DBS, the average percent reduction was 61% . As a sensitivity analysis, we also performed a Wilcoxon sign ranked test, which also found a p-value of < 0.05. Additionally, we found that those patients who chose the cycling burst stimulation parameter had an average 67% reduction in VAS scores, as compared to the continuous burst parameter group, which had an average 48% reduction in VAS scores    Table , Fig. 1.res Fig. . The effres Fig. . HoweverMotor symptoms such as tremor, bradykinesia, rigidity, and postural instability, as well as concurrent pain symptoms significantly impact PD patients’ quality of life. SCS is an emerging technology that can potentially be utilized to treat both the motor and non-motor symptoms such as pain that patients with PD deal with on a daily basis. There are many theories as to how burst SCS leads to an improvement in motor function in patients with PD, and there continues to be ongoing research in the area. While some neurons within the dorsal column generate single action potentials, other neurons in the region fire in a burst of action potentials. These bursts are thought to lead to variations in downstream modulation of the lateral and medial spinothalamic tracts  level, led to improvement in motor function in PD patients. In the current study, 14/15 subjects had SCS placed in the thoracic epidural space. While the mean differences between pre SCS implantation and post SCS implantation groups for motor function  were not statistically different, most patients that were able to complete the tests showed improvement in their completion times for both tasks. Additionally, after removal of outliers, there was a statistically significant improvement in motor function for both groups Table . HoweverSCS could be utilized even after DBS treatment in our study and led to significant pain relief in PD patients. SCS after failed DBS therapy was also able to help a subset of patients in our cohort with motor symptoms, though the difference between the groups as a whole did not show statistical significance. Future studies should be conducted that analyze the use of SCS as a salvage therapy for Parkinson’s disease symptoms after failed DBS therapy.There are several limitations to this study. The patients did not receive the spinal cord stimulator in the exact same spinal location due to differences in presenting pain symptoms. Additionally, not every patient was able to return and complete the TUG and 10 M walk test, which decreased the sample size. However, the majority of patients still had leads placed in the thoracic spine, and the majority of patients were able to complete the questionnaires and tests given in the study. We believe that the data in this study can be helpful to guide future studies that utilize SCS as salvage therapy for Parkinson’s disease to improve the body of literature on the use of SCS in PD patients.In this study, all patients showed a statistically significant improvement in VAS pain scores after receiving SCS. The majority of patients also showed improvements in motor functioning after SCS even after failed DBS therapy. This study thus points to the potential utility of SCS as an option to address both pain and motor symptoms in PD patients who have and have not received DBS therapy.Additional file 1:Supplementary Figure 1. Pre and Post SCS Result for 10 Meter Walk in Patients who RespondedAdditional file 2:Supplementary Figure 2. Pre and Post Spinal Cord Stimulation TUG ResultsAdditional file 3:Supplementary Figure 3. Pre and Post Stimulation TUG Scores Stratified by Stimulation ParametersAdditional file 4:Supplementary Table 1. Other Clinical Characteristics Pre and Post Stimulation


Background: Opioid use has emerged as a leading cause of death in the US. Given that 1 in 300 opioid-naive patients exposed to opioids after cesarean birth will become persistent users, hospitals should strive to limit exposure to these medications. We set out to evaluate whether transitioning to a standardized order set based on multimodal combination analgesic therapy decreases the exposure to opioids after cesarean delivery. Methods: Our health system’s post-cesarean pain management electronic medical record (EMR) order set was changed from standing NSAIDs (Ibuprofen 600 mg every 6 h) and additional acetaminophen and opioid medications  as needed (PRN) to a multimodal combination therapy with acetaminophen (975 mg every 6 h) and NSAIDs (Ibuprofen 600 mg every 6 h) as primary analgesics and opioids PRN (Oxycodone immediate release (IR) 5 mg every 3 h for moderate to severe pain). We performed a retrospective analysis across seven hospitals comparing inpatient opioid use, administration of other analgesics, and severe pain episodes (pain score ≥ 7) between the patients who were treated before and after implementation of the multimodal order set. Chi square and Student t-test were used for statistical analysis with significance determined as p < 0.05. Results: A total of 12,898 cesarean births were included (8696 prior and 4202 after implementation). The multimodal order set was associated with marked decrease in the incidence of post cesarean opioid use , lower average opioid dose , and increased dose of acetaminophen , while severe pain scores were less frequent . Conclusions: Multimodal analgesic therapy for post-cesarean pain management reduces inpatient opioid use while improving pain control. Incorporation of a multimodal order set as a default in the EMR facilitates effective and widespread implementation on a large scale. Obstetric units should consider standardizing post-cesarean pain management orders to include routine (not PRN) multimodal combination therapy with acetaminophen and NSAIDs as primary analgesics. Opioid use has emerged as a leading cause of death in the United States, reaching epidemic proportions in recent years . In factPost-surgical opioid prescriptions are widespread and are frequently the first time a patient will be exposed to opioids. Cesarean delivery is the most common inpatient surgical procedure in the United States, affecting approximately 32% of all births . Most woMultimodal pain therapy utilizes scheduled dosing of several different medications with varying mechanisms of action to control pain while limiting exposure to opioids and thus their potential negative consequences. The American College of Obstetricians and Gynecologists (ACOG) and other societies including the American Society of Anesthesiologists Task Force on Acute Pain Management recommend the use of multimodal analgesic therapy whenever possible for patients with acute postoperative pain ,8,9. NevThe purpose of our study was to evaluate the potential impact of adopting a standardized order set based on multimodal combination analgesic therapy on both opioid usage as well as quality of pain control in the immediate post cesarean delivery period in a large healthcare system with multiple obstetrical units.This is a retrospective analysis of data on all patients who had cesarean delivery between January 2018 and December 2019 in seven hospitals in our health system that has over 30,000 combined annual births and share an enterprise electronic medical record (EMR). Data were extracted directly from the EMR, which contains all post-operative orders, medications administration data , and pain scale assessments. Information regarding medication administration and dosages as well as pain scale assessments are available on patients from admission to discharge.In May 2019, our institution’s post-cesarean pain management order set was changed in our EMR to include a default treatment with combination of agents  based on the recommendations from the ACOG . The anaWe divided our cohort into two groups based on the date of cesarean delivery reflecting the type of post cesarean pain management order set used . The first group consisted of all cesarean deliveries in the 16 months prior to implementing the multimodal analgesic order set (between January 2018 and April 2019), i.e., ‘old’ order set. This group was compared to the group of patients who had cesarean delivery in the first eight months following the implementation of the multimodal analgesic order set (May 2019 through December 2019) i.e., the ‘Multimodal’ order set.The primary outcome was the overall incidence of inpatient opioid use, defined as opioid intake by the patient. Secondary outcomes included stratification of the incidence of opioid use for the first and second 24-h post-operative periods, as well as the last 24 h of hospitalization; the dose of opioid used, expressed in milligrams of oxycodone ; the incidence of administration and dose of other analgesic medications (acetaminophen and ibuprofen); and incidence of severe pain episodes, defined as pain score ≥7 on a 10 point scale.We included in our analyses all cesarean deliveries that occurred during the study period. We excluded cases with incomplete records regarding the cesarean delivery, the administered analgesic medications or dosage, or the post-operative pain score assessment, as well as women with a known opioid addiction. In addition, charts with incomplete data or extreme values of pre-pregnancy body mass index (BMI) (≥60 or ≤18.5), charts with missing maternal age, or charts with maternal age ≥50 were excluded as chart reviews indicate they were likely to represent data entry errors or a unique patient population.Baseline demographic and clinical characteristics such as maternal age, race, ethnicity, pre-pregnancy BMI and weight category, abortion history, parity, and type of cesarean delivery (primary versus repeat) were compared between the two groups as well.t-test was used for continuous variables. Differences in the proportions of inpatient opioid administration over time were evaluated with an interrupted time-series analysis using ordinary least-squares (OLS) regression [p < 0.05, and the proper assumptions were tested and met. All statistical analyses were conducted using Stata 14.2.Pearson’s Chi square was used for categorical variables and presented as odds ratios with 95% confidence intervals, while Student gression . The intThe study received an IRB exemption given the retrospective nature of the analyses and evaluation of de-identified data.‘Old’ vs. Multimodal post cesarean pain management order sets:In the United States, it has become a common practice, as it has been at our institution, to have a pre-selected order set for post-cesarean pain management. The ‘old’ post cesarean pain management order set reviewed in this study included a pre-selected standing treatment with ibuprofen 600 mg every 6 h. Oxycodone 5 mg/acetaminophen 325 mg every 3 h for moderate pain (defined as pain score of 4–6), and oxycodone 10 mg/acetaminophen 650 mg every 6 h for severe pain (defined as pain score 7–10) were pre-selected as PRN order (as needed). It did not include a standing order for acetaminophen . The newIn addition, physicians continued to be able to prescribe “a la carte”, individualized, analgesics (narcotic and non-narcotic) based on clinical judgement and patient specific needs. Of note, oxycodone was the only opioid medication used in both the old and multimodal order sets .There were 13,233 cesarean deliveries during the study period (January 2018 to December 2019). After excluding 335 women with incomplete data, we assessed a total of 12,898 cesarean births, 8696 of which delivered before the implementation of the multimodal order set . There were 4202 cesarean deliveries in the post implementation period between 1 May 2019, and 31 December 2019 . p < 0.0001). The mean total dose of oxycodone for patients who received opioids decreased 27%, from 36.6 mg to 26.7 mg (p < 0.0001).There was a statistically significant difference in the distribution of the specific weight categories between the two groups, although the mean BMI was similar. There were no significant differences in the other demographic and baseline characteristics between the two groups . The comp < 0.001). Furthermore, following this abrupt decrease, a continuous mild reduction in opioid exposure is seen throughout the following eight months since implementation, at a range of 0.25% reduction per week (An interrupted time series demonstrating the average percentage of patients that received opioids in the immediate post cesarean recovery throughout the study period is presented in per week .p < 0.0001). In the same three time periods, significant opioid dose reduction was seen, with a decrease of 17.2% (from 6.5 mg to 5.3 mg), 23.2% (from 17.6 mg to 13.5 mg), and 20.2% (from 18.8 mg to 15.0 mg), in the first, second, and last 24 h periods, respectively (p < 0.0001).Clinically and statistically significant differences were also seen in the incidence of opioid use for each of the 24 h time periods in our stratification: the first 24 h post-operatively ; the second 24 h post-operatively ; and the final 24 h of hospitalization  (p < 0.0001), the actual dose of acetaminophen increased substantially (from 4563 mg to 8422 mg) in the old and multimodal groups, respectively (p < 0.0001). Substantial increases in acetaminophen doses were seen in both patients that were exposed to opioids , as well as in patients that did not take opioids . Significant increase in the dose of acetaminophen were noted for each of the 24 h time periods with dose increase from 802 mg to 1897 mg, from 1355 mg to 2656 mg, and from 1636 mg to 2796 mg, in the first, second, and last 24 h periods, respectively. The difference in ibuprofen dose was statistically but not clinically significant .Although the incidence of administration of acetaminophen was high in both groups, and increased only mildly . Similarly, statistically significant improvements in pain control based on pain scores were further demonstrated during the first and second 24 h post-operative periods, as well as the last 24 h of hospitalization.Severe pain scores decreased from 56.6% with the old order set to 46.3% with the new, multimodal, order set , while the average opioid dose decreased by 27% . Of interest, the new, multimodal order set led to improved pain control, with severe pain episodes (pain score ≥ 7) decreasing by 18.2%, from 56.6% with the old order set to 46.3% with the multimodal regimen .After implementing a standardized post-cesarean order set for pain management employing multimodal combination therapy, we found a substantial reduction in both the rate and dose of opioid administration. Post-cesarean opioid use decreased by 32.7%, from 67.5% with the old order set to 45.4% with the multimodal order set  at a dose of 0.15–0.3 mg. In cases where epidural anesthesia was already administered during labor, the Duramorph dose used was 3–4 mgIn conclusion, we demonstrated that a standardized post-cesarean order set based on multimodal therapy resulted in substantially decreased exposure to opioids while simultaneously improving pain scores. Embedding such order sets as a default for post-cesarean pain management in the EMR facilitates effective and widespread implementation on a large scale. Hospitals should consider standardizing post-cesarean pain management orders in their EMR to include multimodal combination therapy with acetaminophen and NSAIDS as primary analgesics.


BackgroundRecurrent lumbar disc herniation (RLDH) is one of the most common causes of chronic low back and leg pain. Although surgical treatment has high success rates in primary lumbar disc herniations, recurrence is not an uncommon clinic condition after the surgery. Considering the recurrent surgeries have lower success rates and higher risks, such as dural tear and nerve injury, alternative treatment modalities are needed for RLDH patients. Epidural steroid injections (ESI), particularly transforaminal steroid injection (TFESI) and caudal steroid injection (CESI), which are the alternative treatments to surgery, have not shown reasonable results in RLDH separately. In this study, we aimed to investigate the effects of combined TFESI and CESI (TFESI + CESI) treatment, which has been found successful in primary lumbar disc herniation (PLDH) and on pain control and quality of life in RLDH patients for the first time.Materials and methodsA total of 71 patients, who had ESI treatment as only TFESI or TFESI + CESI because of RLDH in our clinic between March 2017 and February 2020, were investigated retrospectively. The visual analog scale (VAS) leg, VAS back, and Oswestry disability index (ODI) were used to assess leg pain, low back pain, and limitation of daily routine activities. Each assessment was done before the intervention and repeated at the third week, the third month, and the sixth month of injection, and the results were noted.ResultsOut of 71 patients, 38 were female and 33 male. Patients were divided into two subgroups according to the applied ESI methods as only TFESI (n = 32) and TFESI + CESI (n = 39). In the only TFESI group, the mean VAS leg score was 7.84, 4.63, 5.40, and 6.19 before, at the third week, the third month, and the sixth month of the injection, respectively. Also, in this group, the mean VAS back score was 8.06, 4.16, 4.88, and 5.97; the mean ODI score was 55.81, 34.31, 37.5, and 49.04 in the same respect. In the TFESI + CESI group, the mean VAS leg score was 8.20, 2.87, 3.64, 4.23; mean VAS back score 8.03, 3.05, 3.90, 4.08; mean ODI score 56.56, 28.05, 30.21, 33.64 before, at the third week, third month, and sixth month of the injection, respectively. The mean of the initial VAS leg, VAS back, and ODI scores was not found to be statistically significantly different between the two groups. The mean of all VAS leg, VAS back, and ODI scores was found to be lower in the TFESI + CESI group than the only TFESI group at each third-week, third-month, and sixth-month controls, and these differences were statistically significant. ConclusionOur study demonstrates that TFESI + CESI treatment is an effective non-surgical treatment for RLDH. Considering the higher risks and lower success rates of recurrent surgeries, TFESI + CESI can be a potential treatment option for RLDH patients. Recurrent lumbar disc herniation (RLDH) is one of the most common causes of failed back surgery syndrome (FBSS) . DespiteThe management of RLDH is challenging, and there is no certain data in the literature about choosing the most appropriate treatment option for these patients . AdditioEpidural steroid injections (ESI), which are among the minimally invasive treatment options and found more effective than conservative treatment in lumbar disc herniations , can be Although the effectiveness of all three methods in PLDHs has been reported previously, there is a limited number of studies on RLDHs in the literature -9. In thIt has been demonstrated that the combined application of ESIs as TFESI + CESI, which are known to be effective when applied separately in PLDHs, increases the effectiveness of the treatment . SimilarA total of 71 patients who were referred to our clinic between March 2017 and February 2020 and were applied only TFESI or combined TFESI + CESI treatment due to RLDH were investigated retrospectively. All participants were informed in detail and their written informed consent forms were signed before the procedure.Patient inclusion and exclusion criteriaPatients presented with low back and unilateral or bilateral leg pain who were found to have RLDH in lumbar MRI scans Figure  and theiPatients with lumbar degenerative spinal stenosis, spondylolisthesis, facet joint pain, adjacent segment degeneration, sacroiliac joint pain, discitis, pseudoarthrosis, arachnoiditis, segmental instability, spinal trauma, less than three months of complaints, partially benefited from medical treatment, infective or oncological disease, previous history of lumbar ESI treatment, severe metabolic or systemic disorders, required surgical treatment due to worsening neurological deficits and those who did not come to follow-ups were excluded from the study.Intervention procedureTFESI or TFESI + CESI procedures were performed only once for each patient by the same surgeon in the prone position. Blood pressure, electrocardiogram, pulse rate, and respiratory rate, oxygen saturation were monitored. Patients were not routinely sedated, and sedation with midazolam was used when necessary. After the procedures, patients were followed up for four to six hours in the recovery room to assess possible early complications. No major complications were observed. All patients were discharged within six hours after the procedure and hired for controls. Non-steroidal anti-inflammatory drugs were not prescribed to patients at discharge.TFESI ProcedureFollowing skin antisepsis and sterile dressing, the vertebra level to be injected was determined in the prone position with C-arm fluoroscopy in the A-P position. C-arm fluoroscopy was turned to a 15-degree oblique position and the intervertebral foramen was visualized. For local anesthesia, 1 mg 1% lidocaine was applied to the skin and subcutaneous tissue. The TFESI procedure was performed using the preganglionic approach with the technique described by Lee et al. . Under tCESI ProcedureFollowing skin preparation and sterile dressing in the prone position on the operating table, sacral hiatus was identified and local anesthetic  was applied to the overlying skin and underlying ligaments. A 22-gauge, 90-mm spinal needle  was placed between the sacral cornua with a 45-degree angle under the C-arm scope control. After the control, the needle was directed more cranial, horizontal, and parallel to the ground then inserted through the sacrococcygeal ligament and entered into the caudal epidural area about 1-2 cm. After checking for bleeding or cerebrospinal fluid leakage by an aspiration test, the position of the spinal needle was confirmed by injecting 1 ml contrast agent   score as VAS leg and VAS back separately. The participants scored their pain severity with values between 0 and 10 for this scale. Patients were asked to score 0 points for no pain and 10 points for the most intense pain of their life. The limitation of daily routine activities was assessed by the Oswestry Disability Index (ODI). ODI is a questionnaire that assesses the pain caused restriction with 10 items, including pain intensity, changing degree of pain, personal care, sleep quality, social life, and abilities of sitting, walking, standing, lifting, and traveling. Each subheading has six choices that correspond to scores ranging from zero to five according to the amount of disability. Scores are summed and then multiplied by two for evaluating over 100 points and higher scores point out more severe disability.All patients were evaluated in the preoperative period and the postoperative third weeks, third months, and sixth months.Statistical analysisDescriptive statistics were used for continuous variables . The paired t-test was used to compare the pre-injection and post-injection results of the TFESI + CESI group and the TFESI group average pain. A probability (p) value of <0.05 was considered statistically significant. All statistical analyses were performed using the IBM, SPSS Statistics version 22 .A total of 85 patients were included in our study for a period of 35 months, but 14 patients were excluded from the study because they did not continue their follow-up. Thirty-eight (53.5%) of the remaining 71 patients were female and 33 (46.5%) were male. While 39 of 71 patients had both TFESI and CESI treatment in the same session, only TFESI was applied to 32 patients. Patients were divided into two groups according to the treatment they received. There was no statistically significant difference between the groups in terms of gender and affected disc level. The mean age of the only TFESI group was 49.7 (SD 12.46) and the TFESI + CESI group was 53.6 (SD 13.04) (p=0.194)  before the injection, 4.63  at the third week, 5.40  at the third month, and 6.19  at the sixth month of the injection. The mean of the VAS leg score was 8.20 , 2.87 , 3.64 , and 4.23  at the first appointment, three weeks, three months, and six months after the injection respectively for patients who received combined TFESI + CESI. Although there was no statistically significant difference between the VAS leg scores of the TFESI and TFESI + CESI groups at the first appointment (p =.0128), the mean of the VAS leg score of TFESI + CESI patients was found to be statistically significantly lower than the only TFESI patients at the third week, third month, and sixth-month controls (p < 0.0001)  at the beginning, 4.16  at the third week, 4.88  at the third month, and 5.97  at the sixth month of the injection. In the TFESI + CESI group, the mean VAS back score was 8.03 , 3.05 , 3.90 , and 4.08  in the same order. There was no statistically significant difference between the mean VAS back scores of the groups before the intervention (p=0.897), and the decrease of mean VAS back score after the injection was statistically significant in both groups. This decrease was more significant in the TFESI + CESI group at the controls   and the TFESI + CESI group was 56.56 (SD 7.21). The mean of the ODI score at the third week, third month, and sixth month of the injection was 34.31 (SD 7.86), 37.5 (SD 8.39), and 49.04 (SD 7.13) for the TFESI group and 28.05 (SD 4.84), 30.21 (SD 5.14), and 33.64 (SD 5.52) for the TFESI + CESI group, respectively. There was no statistically significant difference between the mean pre-interventional ODI scores of the groups (p = 0.897). Although the decrease of the mean ODI score as compared to the initial score was seen at all the third-week (p = 0.0003), third-month (p < 0.0001), and sixth-month (p < 0.0001) controls in both groups, the TFESI + CESI group was found to be with lower mean ODI scores at each control than the only TFESI group (Figure The persistent pain after discectomy is contributed by recurrent disc herniation, epidural fibrosis, spinal canal stenosis, laminectomy caused instability, and myofascial pain syndromes . Also, rESI, one of these treatment options, can be applied by various methods, which especially include TFESI and CESI. Steroids injected into the epidural space reduce intraneural edema and venous congestion and thereby alleviate the ischemia and pain by direct and indirect actions . The supThere are many publications indicating that TFESI is the most effective and preferred ESI method for PLDHs in the current literature -8,16. ThOne of the other types of ESIs is CESI, which has less dural injury risk especially in patients with previous lumbar surgery history, and enables reaching the epidural area easier than both TFESI and IESI. Also, CESI has been found to be safer than IESI and TFESI for patients with bleeding diathesis caused by anticoagulant usage or coagulopathy . CESI coIn CESI, steroids are administered through the caudal hiatus and maybe spread into areas beyond the desired target . Also, tOne of the important points for ESI treatments is the effective duration of injections. Although TFESI had a longer effective duration than CESI , while CHypertrophied structures in the spinal canal block the effective distribution of steroids to the anterior epidural area in both TFESI and CESI -26. In aThere are many publications that investigate the efficiency of ESIs for PLDHS, but knowledge of RLDHs is limited in current literature. Karamouzian et al. compared the results of TFESI and CESI in RLDHs . They suThough there were no studies to the best of our knowledge for combined ESI treatment in RLDHs, there are limited studies that focused on the combined ESI treatment for PLDHs in current literature. One of these is Kircelli’s publication that compared the results of patients who had been treated by TFESI + CESI and TFESI alone. Additionally, they reported that combined treatment had better outcomes with increased quality of life and pain control in short- and long-term periods . The undPercutaneous adhesiolysis, which is a technique used for gaining epidural scarring lysis in patients with the lumbar post-surgery syndrome, caused permanent leg and low back pain. This technique is based on the usage of local anesthetics, steroids, hypertonic sodium chloride solutions, and hyaluronidases. Because the separate application of ESI methods was not found to be sufficient for lumbar post-surgery syndromes, including recurrent lumbar disc herniations, percutaneous adhesiolytics have come to the fore in this area and these agents have been found to be more effective than the separate application of ESIs particularly CESI . AlthougThere are some limitations to this study. First of all, the study was carried out retrospectively. Also, only one type of TFESI and CESI approach was applied to patients, variants of the TFESI and CESI application methods were not considered, and their individual results could not be evaluated. Further studies can be planned regarding these points, for gaining wider knowledge.Considering the decreased effectiveness and increased risks of surgery, alternative treatment options are necessary for RLDHs. ESIs are frequently used and non-surgical treatment modalities in current clinical practice for lumbar disc herniations. The combined usage of ESI methods has become a current issue with higher success rates in PLDH but, to our knowledge, there were no studies that investigate their efficiency in RLDH previously. Our study demonstrates that combined TFESI + CESI can be a beneficial treatment option for RLDH patients whose management is challenging. Before planning further invasive treatment methods, combined ESI application may be useful for RLDH patients.


Failed back surgery syndrome (FBSS) is a commonly encountered disease after lumbar surgery. There are many cases where it is difficult to choose a treatment because no specific cause can be found. Nevertheless, according to recent reports, adhesiolysis has shown reasonable evidence. However, considering its poor cost-effectiveness, adhesiolysis cannot be used as the first line of treatment. FBSS patients often suffer from chronic pain; accordingly, they become frustrated when this treatment produces a poor response. Therefore, before the procedure, the target group must be selected carefully. We sought to identify the pre-procedure factors predicting the effect of adhesiolysis in FBSS. A total of 150 patients were evaluated and analyzed retrospectively. Of these 150 patients, 69 were classified as responders three months after the procedure (46%). The outer diameter of the catheter during the procedure and grade of foraminal stenosis were correlated with the procedure effect. In conclusion, of the 2.1 mm diameter of the catheter, 1.7 mm of it was used during the procedure, and the milder the foraminal stenosis, the greater the pain reduction effect was three months after the procedure. A significant proportion of patients undergoing lumbar spine surgery to treat low back pain or radicular pain have experienced symptoms persisting or recurring after surgery ,2,3,4. TPain physicians often confront FBSS patients in a clinical setting, but treatment is difficult due to complex and heterogeneous pathophysiology ,12. AnotClinicalTrials.gov (KC20RISI0917). All participants gave informed consent, and this study was conducted in accordance with the Declaration of Helsinki.We reviewed the medical records of patients who underwent adhesiolysis using a steerable catheter under the diagnosis of FBSS from 1 January 2013 to 30 June 2020 at the pain clinic of Seoul St. Mary’s hospital. The study protocol was approved by the Ethical Committee of the Seoul St. Mary’s Hospital (KC20RISI0665). This trial was registered on 30 November 2020 at All patients received lumbar magnetic resonance image (MRI) prior to undergoing adhesiolysis. When considering adhesiolysis, the pathology that can explain the cause of persistent low leg and/or back pain in lumbar MRI was confirmed in advance. All patients underwent conservative treatment such as exercise and epidural injection before adhesiolysis. The inclusion criteria were as follows: (1) at least 20 years of age; (2) a history of spine surgery; (3) chronic leg pain and/or back pain for at least three months after lumbar surgery; and (4) failure to respond to previous epidural injection combined with exercise and pharmacotherapy. The exclusion criteria were as follows: (1) presence of coagulopathy; (2) presence of malignancy; (3) presence of other causes of symptoms ; (4) any evidence of central nervous system injury; (5) other procedures such as cervical neuroplasty or nerve block together with lumbar neuroplasty; and (6) follow-up loss before the third month of the procedure. Finally, 150 patient charts were selected and reviewed.Adhesiolysis was performed under fluoroscopic guidance. Before starting the procedure, the patient’s intravenous access should be secured, and pretreatment with antibiotics should be performed. The patient’s vital signs were monitored from the beginning to the end of the procedure. The patient was in a prone position, and a pillow was placed under the abdomen to minimize lumbar lordosis. After the position of the fluoroscope was adjusted so that the lumbosacral area could be viewed in both anteroposterior and lateral views, local anesthetics (1% lidocaine) were infiltrated by determining a needle insertion site around the sacral hiatus. After the guide needle was inserted via the sacral hiatus, approximately 3 mL of diluted contrast medium was injected to obtain the epidurogram of each patient. If contrast flow reveals suspicion of intravascular injection, the needle must be repositioned. The epidurogram was assessed to identify filling defects. Actually, the target level of adhesiolysis is set in advance by taking together the location of the filling defect and the patient’s symptomatic dermatome and lumbar magnetic resonance image (MRI) findings. After determining the goal, the catheter advances through the guide needle .®, GSmedical, Chungcheongbuk-do, South Korea; (2) Biovision®, Technologies LLC, Colorado, United States; and (3) STREED plus®, Seawon Medi-Tech Co., Ltd., Gyeonggi-do, South Korea) was used, and catheter selection was determined according to the operator’s preference. All catheters used were products that could bend the tip of approximately 1 cm. When the catheter wheel mounted on the operator’s handle was turned, navigation of the catheter tip became easy. The procedure was performed by specialists skilled in neuroplasty. To reach the target site, the catheter was manipulated by pushing, pulling, and rotating. When the catheter tip reached the target, mechanical adhesiolysis was performed through gentle side-to-side positioning of the catheter. At this time, pain may be induced in the same location as the patient felt previously. Then, when 1 cc of diluted contrast was shot, it was confirmed that the filling defect was resolved. The contrast flow appeared in the shape of a nerve root near the neural foramen and an epidural space shape in the central region. When it was confirmed that vascular injection was also excluded, a mixture of 10 cc of 1% lidocaine and 5 mg dexamethasone and 1500 IU hyaluronidase  was divided and injected separately into each target.One of three types of steerable navigation catheters ((1) Episoln = 81, 54%).Occasionally, in some patients, the catheter was attempted to enter the area where the filling defect was observed on the epidurogram, but the catheter tip could not reach the area, even after repeated attempts. It was clear that if the catheter tip did not reach the target, both mechanical and chemical adhesiolysis could not be performed, so clinical improvement would not be possible. Therefore, only in these cases was a transforaminal epidural injection additionally performed at the level where adhesiolysis was not possible at the end , and past medical history were obtained through medical records. Whether or not the patient had performed the nerve blocks  during the 3-month follow-up period was also determined through medical records. Simple radiography and MRI were also reviewed to assess the location and severity of lumbar spinal stenosis. The severity was graded based on the standard classification ,31. For The NRS score at three months after adhesiolysis was determined through a chart review. After three months, patients whose NRS decreased by two points compared to before the procedure were classified into the responder group. Patients who received lumbar radiofrequency ablation or a spinal cord stimulator after neuroplasty or transferred to the department of surgery were also defined as nonresponders. Patients with increased oral opioid dose were also classified as nonresponders. According to this definition of response, patients were divided into responders and nonresponders three months after the procedure.t-test and are presented as the means with standard deviations. Categorical demographic data were analyzed using a chi-square test or Fisher’s exact test and are expressed as numbers and percentages. A two-tailed p-value < 0.05 was considered to be statistically significant. All data were analyzed using SPSS version 24.0 .Continuous demographic data were analyzed using the Student’s A total of 150 subjects met the inclusion criteria. At the three-month follow-up, 69 subjects were classified into the responder group (46%), and 81 subjects were classified into the nonresponder group (54%) . The basp = 0.017) and the foraminal stenosis grade (p = 0.039) showed significant results. The catheter diameter used at the time of the procedure was 2.1 mm rather than 1.7 mm, and the milder the degree of foraminal stenosis, the greater the pain three months after the procedure. If the catheter had an external diameter of 2.1 mm, the success rate at three months of the procedure was 56.5%, and for 1.7 mm, the success rate was 37%. In patients with mild cases of foraminal stenosis, the success rate of neuroplasty at three months was 56.4%; in those with moderate cases, it was 40.6%; and in those with severe cases, it was 28.6%. The grade of central stenosis showed no significant relationship with the effect of the procedure (p = 0.428). The intervention characteristics were not significantly different between the two groups.The clinical data of nonresponders and responders at three months after the procedure are shown in p = 0.568). When transforaminal epidural injection was performed after adhesiolysis, disc injection rarely occurred. The number of cases with vascular injection was not counted when the needle was readjusted to exclude contrast vascular absorption, so it was very rare. There were no cases of severe neurologic catastrophic complications such as motor weakness.The complications observed during lumbar neuroplasty are shown in What is exceptional to note in our report is that the preprocedural effect predictors were presented when adhesiolysis was administered in FBSS, and the analysis was performed by including factors that were not covered in papers that previously presented the effect predictors of adhesiolysis in FBSS ,33,34.According to the results of the study, when adhesiolysis was performed in FBSS patients, the milder the foraminal stenosis on lumbar MRI, the better the pain reduction effect after three months of the procedure (56.4%). The foraminal stenosis grade increased, and the outcome of the procedure tended to decrease. However, even with severe foraminal stenosis, 28.6% were successful responders. Therefore, even severe adhesiolysis is difficult to regard as contraindicated. Among the existing studies, no studies have included the grade of central stenosis and foraminal stenosis as analysis factors while analyzing the factors for predicting effects when performing adhesiolysis in the FBSS patient group. Oh et al.  reportedIn our study, a total of three types of steerable catheters were used. There were two types of 1.7 mm external diameter catheters, Biovision and Episol, and one type of 2.1 mm external diameter catheter, the ST REED Plus. The choice of catheter was determined by the availability and preference of the operator at the time of the procedure. Since the 1.7 mm outer diameter catheter is relatively thin, it has the advantage of easy access even in patients with narrow caudal space. It was estimated that the 2.1 mm outer diameter catheter was relatively rigid so that thick adhesions could be mechanically lysed with stronger power. This is a new report because existing papers have unified the type of catheter as one. However, unlike expectations, there was no correlation between the catheter external diameter and the occurrence of dura puncture.The basic treatment guidelines of our pain clinic center for FBSS patients are described by Gatzinsky et al. , which iThe limitations of this study are as follows: first, follow-up loss was selected as the study exclusion criterion. Follow-up loss may be due to improved symptoms or because the procedure did not work. Therefore, the patient groups with follow-up loss were not included in the analysis. Since the percentage of the follow-up patient group occupied 78 patients, this may be a factor that hinders reaching an accurate conclusion. Second, because the pain duration of the target patient groups was long, patients often did not remember exactly when the pain started. Data collection was based solely on the patient’s statement. The average pain duration value was 72.1 months. As the pain period is long, the accuracy of the pain duration decreases, which can be a factor that prevents accurate conclusions from being reached. In a similar preliminary study that reported that there was a correlation between pain duration and a decrease in pain score six months after the procedure when neuroplasty was performed in FBSS, the patient’s pain duration median value was 36 months . Third, Although FBSS is a refractory disease that must be treated with a multidisciplinary approach, adhesiolysis using a steerable catheter could be an effective treatment. When adhesiolysis was performed in the FBSS patient group, the treatment effect was better in cases with mild foraminal stenosis on lumbar MRI. The catheter used during the procedure should be able to reduce the pain more than three months after the procedure when using a 2.1 mm catheter rather than a 1.7 mm external diameter.