Many health care professions have reacted swiftly to the COVID-19 pandemic. In-person care has been ramped down and telemedicine/telehealth has been thrust to the forefront of clinical care. For people living with chronic pain and often concomitantly dealing with opioid-related issues, this is a time of great stress. With population-wide movements to shelter in place, people living with pain are more isolated, more stressed, and more vulnerable to mental health concerns like depression and anxiety that can increase pain-related suffering. This article presents two case reports of patients struggling with chronic pain and opioid dependence in which a telemedicine-based buprenorphine-naloxone conversion was chosen as a treatment option by two Canadian programs: The Transitional Pain Service at the Toronto General Hospital in Toronto, Ontario, and The Opioid Deprescribing Program in Calgary, Alberta. Both cases presented highlight the use of telemedicine during the COVID-19 pandemic and suggest that there will be substantial need for these services well beyond the apex of the crisis. A buprenorphine-naloxone home induction protocol is presented and we provide insight into important lessons learned regarding the appropriate selection of patients with chronic pain struggling with opioid use disorder for buprenorphine-naloxone conversion. The provision of health care during the COVID-19 pandemic has rapidly forced practitioners to evolve novel health care practices, and these changes will have long-term implications. Most health care resources have been redirected with the overarching goal of protecting society, while ramping down in-person care in the hopes of “flattening the curve” and stopping the rapid spread of this deadly virus. Consequently, patients are enduring significant delays to their care pathways, having had elective procedures—as well as potentially life-saving procedures, such as cancer surgeries—postponed for weeks and potentially months. The debate over which patient visits/procedures are considered elective vs. essential changes daily. Practice guidelines are urgently needed, and experts have begun to publish treatment recommendations—for example, an expert panel of pain physicians, psychologists, and researchers from Europe and North America recently published chronic pain practice recommendations to guide treatment during COVID-19.2 this is a time of great stress. With population-wide movements to shelter in place, people living with pain are more isolated, more stressed, and more vulnerable to mental health concerns like depression and anxiety that can increase pain-related suffering. In addition, patients do not have access to in-person services like physiotherapy and some interventional procedures during this time. With ongoing global supply chain issues,3 the fear of running out of medications is significant among patients consuming prescription opioid medications. Long-acting opioid formulations are on back order without a clear indication of when that might be remedied. This shortage can have severe consequences, both physical and psychosocial. Some patients may suffer in isolation as they cope with significant opioid-related withdrawal; others may not be able to tolerate this distress and turn to high-risk illicit opioids in an attempt to mitigate their withdrawal symptoms and distress.4For people living with chronic pain and often concomitantly dealing with opioid-related issues,essential service. Physicians’ offices cannot simply close and abandon their patients. Interdisciplinary pain treatment must instead be triaged into levels of care with clear indications for in-person and remote/virtual intervention. Services that must be delivered face-to-face  can be prioritized for in-person delivery, and clinical care that can be conducted remotely should be adapted to virtual delivery in order to reduce risk of COVID-19 transmission for patients and providers alike. The risk–benefit analysis for in-person care has been abruptly turned on its head. Accordingly, a key question for clinicians now is how clinical pathways can be effectively adapted for telemedicine and virtual health care. Over the past several years, telemedicine had been slowly progressing as a means of reaching rural clientele5; however, now its role must rapidly expand to reach patients who are practicing physical distancing to prevent the spread of COVID-19.For people living with chronic pain who take prescription opioid medications, health care delivery is an In addition to practice-related questions, this rapidly emerging new paradigm raises questions about what technological means should be used by health care providers to communicate remotely with patients, as well as remotely with one another. Health care systems around the world are being thrust into utilizing existing telephone infrastructure and web-based video conferencing platforms, including those developed by public health institutions  and those developed commercially .This article describes care pathways for buprenorphine-naloxone induction when in-person care is not the best option. Two patient case reports will be presented, the first treated by the Transitional Pain Service (TPS) at the Toronto General Hospital. This began with an in-person visit prior to the COVID-19 shut down and rapidly turned into a case needing an interdisciplinary health care model with virtual visits. The second case is an example of a home induction of buprenorphine-naloxone in a person living with chronic pain during the COVID-19 shutdown illustrating an established care pathway developed by the team at the Opioid Deprescribing Program in Calgary. The initials used throughout the article are pseudonyms to protect the patients’ identities. Practice issues and lessons learned will be discussed, with the hope that the home induction protocol we present may continue to be used once the current pandemic has ended. A written informed consent form was signed by each patient who agreed to the publication of the present case report and who also reviewed the article and approved the details of their case.C.D. is a 67-year-old woman who had to reduce her work commitments as of 2014 due to pain-related disability after developing postherpetic neuralgia (PHN) of her face and head. On presentation to the TPS clinic at the start of the COVID-19 pandemic in early March 2020, her pain complaint was mainly on the right side of the head in the cranial nerve V1 distribution of the trigeminal nerve. Her pain was most often in the severe range, with the lowest pain severity score in the moderate range at 6/10 on the 0–10 pain intensity numeric rating scale. Previous visits with neurologists had ruled out migraines or trigeminal neuralgia.Over the years, C.D. had tried gabapentin to a maximum dose of 3600 mg/day, pregabalin without convincing results, levetiracetam (intolerant due to adverse effects), and carbamazepine 900 mg/day with little benefit. A recent trial of 0.5 g/day of physician-authorized THC-dominant cannabis via vaping worsened her symptoms and caused paranoid hallucinations. CBD oil 20 mg/ml 0.5 ml TID also did not improve her symptoms. A neurosurgeon had suggested the possibility of peripheral neurostimulation; however, because results were often mixed, C.D. decided against it. At the time of the initial assessment, C.D. was taking 60 mg of oxycodone daily, which she would supplement with a carbamazepine tablet (100 mg) on the occasional day when her pain was excruciating. Accordingly, her morphine equivalent dose at TPS intake was 90 mg/day.6 in which vomiting is triggered by either opioid tapering or consuming oxycodone tablets. Treatment options were discussed, including rotation to another opioid or conversion to buprenorphine-naloxone. The shared decision was made to initiate the transition to buprenorphine-naloxone. The plan was that once she was stable on a dose of buprenorphine-naloxone, we could target a multimodal plan for her PHN symptoms.C.D. reported that she wished to stop using oxycodone, in part because it was providing only 10% to 20% pain relief and in part because she was concerned about dependence, but she could not taper the oxycodone (even very slowly) because it would induce vomiting. Indeed, at the initial visit to the TPS she kept a container close by in case she needed to vomit, which she did intermittently. It appeared that in addition to severe PHN in the cranial nerve V1 distribution, she had developed an opioid-induced cyclical vomiting syndrome7 of 5. By midday her COWS score was 9 and she displayed increasing restlessness and distress. Y.K. then initiated the first 2 mg dose of sublingual (SL) buprenorphine-naloxone. By 5 p.m. that afternoon (after one of the buprenorphine 20 μg patches had been removed), her COWS score had increased to 14. She was given another 4 mg of buprenorphine-naloxone, discharged home on the remaining 20 μg/h buprenorphine patch, and given instructions to take additional 2 mg tablets of buprenorphine/naloxone as needed overnight to manage her withdrawal symptoms up to a maximum of 16 mg.Given our experience with previous inductions, we selectively chose to start patients on a buprenorphine transdermal patch prior to a buprenorphine-naloxone induction to mitigate some of the anticipated adverse induction withdrawal symptoms, in particular patients consuming less than 90 mg/day. Two 20 μg/h buprenorphine patches (40 μg/h) were placed on her arm 3 days prior to the buprenorphine-naloxone induction. The rationale for this treatment stemmed from H.C.’s experience with a patient who did not need to take an oral buprenorphine-naloxone tablet on the day of the planned induction when converting from low-dose oxycontin/oxycodone  with placement of a transdermal buprenorphine patch. C.D. was advised to stop taking oxycodone at 8 p.m. the night before (12 h prior to the planned induction). On the morning of the induction, C.D. presented to the TPS clinic with a Clinical Opioid Withdrawal Score (COWS)8 Microdosing can be done either by the sublingual route8 or the transdermal route presented in our case report.10 Recently, rapid induction of microdosing by the sublingual route has become more common.12 The advantage of the rapid induction microdosing is that it takes 3 to 5 days, in comparison to the Bernese method, which usually takes more than 10 days. The microdosing regimens explained in the above literature tend to occur in classic inpatient settings. However, it has become clear that the microdosing induction technique is manageable and effective in an outpatient setting. A less frequent dosing regimen may be more practical for outpatients.The introduction of the buphrenorphine patch prior to the initiation of oral buprenorphine-naloxone for C.D. is an example of a microdosing technique. Traditional induction of buprenorphine-naloxone requires patients to be in mild to moderate withdrawal from other opioids before administration of buprenorphine-naloxone. This period of opioid withdrawal can be poorly tolerated by patients and may discourage induction, improving retention in people with opioid use disorder. Furthermore, tapering of the full agonist without replacement with partial μ-opioid agonist bears the risk of relapse to illicit opioid use. The Bernese method describes a microdosing induction regimen for buprenorphine that overcomes this opioid withdrawal effect.Our typical clinical care pathway would have been to see C.D. in person, in clinic, the following morning. However, given the rapidly escalating concern over COVID-19, the hospital mandated that all face-to-face patient visits to the clinic be canceled and clinical staff transition to seeing patients using telehealth services.C.D. was called the following morning to inform her of the unanticipated COVID-19 mandate and to monitor her progress. C.D. reported that the induction had not progressed smoothly and that she was in significant distress. Several hours after leaving the TPS clinic the previous day, she presented to her local emergency department. The emergency physician astutely ascertained that she was dealing with heightened opioid withdrawal, gave her another 2 mg tablet of buprenorphine-naloxone, and discharged her home to continue the induction according to our previous instructions. She had taken another 2 mg buprenorphine-naloxone overnight but during H.C.’s telephone call with her in the morning she continued vomiting throughout the conversation, so it was decided that C.D. would take the entire 12 mg dose that morning. A requisition for a prescription of 12 mg/day SL buprenorphine-naloxone was sent to her pharmacy (1 × 8 mg/2 mg and 2 × 2 mg/0.5 mg tablets). A follow-up call was made that day to C.D. at 12 p.m., by which time she reported that she was starting to feel better. Later that evening as withdrawal symptoms intensified, C.D. took another 2 mg buprenorphine-naloxone. Given the rocky nature of this induction, the hope was that she was over the worst and was heading toward a smooth zone moving forward.On the third morning after the start of the buprenorphine-naloxone induction, around 9 a.m., H.C. received a distressed mobile communication from C.D. She explained that she was not able to tolerate the large 8 mg tablet. It caused her to gag when placed under the tongue; hence, she had spit out her morning dose. During the telephone assessment, it was unclear how much of the dose she had absorbed. She stated that she was trembling and alone , vomiting continually, and unable to leave her bed. At this point, and in the midst of COVID-19, H.C. was struggling to provide the support C.D. required and enlisted the help of the TPS multidisciplinary team (Y.K. and A.W.), who were both in self-isolation, as well as his colleague (R.T.), who resides in Alberta. These colleagues agreed to an impromptu teleconference meeting to discuss the challenges of the current case. Following the meeting, H.C. called C.D. to present a path forward that included a modified pharmacological approach and psychological intervention with A.W.On the call to C.D., she reported that the day before, she had left her buprenorphine-naloxone tablets in a downstairs location in her house and was currently unable to navigate the stairs to retrieve them given how weak and unstable she felt. H.C. and C.D. devised a plan for one of C.D.’s neighbors to help by bringing C.D.’s 2 mg tablets from the downstairs location to the upper floor, leaving the medication outside C.D.’s bedroom door. Once her neighbor had departed, C.D. would retrieve the tablets. This plan, for the most part, maintained the physical distancing polices that the provincial government had implemented.13Because C.D. was not able to take an 8 mg tablet, the team’s plan was to titrate to 16 mg buprenorphine-naloxone, in 2 mg dose escalations, from the 14 mg dose the day before. Given the uncertainty of how much of the 8 mg tablet had been absorbed in the morning, H.C. instructed C.D. to start afresh and take 5 × 2 mg tablets over the next hour with a goal to consume three more 2 mg tablets prior to bedtime for a total daily dose of 16 mg. A telephone call changing her prescriptions from 8 mg to 2 mg tablets of buprenorphine-naloxone was made to the pharmacist who facilitated this change. During the COVID-19 pandemic, Health Canada issued a temporary exemption for patients, practitioners, and pharmacists prescribing and providing controlled substances that enables telephone orders.H.C. also informed C.D. that A.W. had agreed to provide her urgent psychological intervention sessions to help her get through this extremely distressing period. That Friday afternoon A.W. reached out to C.D., and by the following morning C.D.’s vomiting had subsided for the first time in weeks. Over the course of the weekend, C.D. reported that she was able to get out of the house , tend to her horses, and walk her dog, significant achievements relative to the pre-induction and immediate postinduction periods.C.D. was stable on 16 mg buprenorphine-naloxone a day after the oxycodone to buprenorphine-naloxone conversion, and there was complete resolution of her nausea and vomiting symptoms. However, she reported that she was now plagued by an enormous amount of anxiety, with panic attacks four to five times a day. One of the adverse effects associated with buprenorphine-naloxone is significant anxiety, which may be related to an increase in limbic tone. Given her significant emotional distress, a shared decision was again made to reduce the buprenorphine-naloxone dose to 14 mg/day with the goal of getting the dose down to 8 mg, at which point her anxiety might be reduced and the focus would shift to starting neuropathic pain medications for her PHN. Unfortunately, by the following morning, the vomiting cycle had resumed, and it was apparent that C.D. was exquisitely sensitive to changes to her opioid dose. C.D. once again called upon the services of A.W. and we immediately reinstated the 16 mg/day dose.14 In addition, the ACT matrix is used as a visual teaching tool to communicate ACT principles.15 Skills from mindfulness and acceptance-based therapies beyond acceptance and commitment therapy, such as dialectical behavior therapy (DBT),16 are incorporated as appropriate. Finally, in this case, clinical hypnosis was used to treat nausea and vomiting.For people living with pain and opioid dependence, psychological care during buprenorphine-naloxone induction generally is brief . In terms of treatment techniques, sessions are modeled on the focused acceptance and commitment therapy (FACT) protocols developed by Kirk Strosahl and colleagues for use with medical patients.A range of techniques are used, but the goal is quite singular: to help patients tolerate the intense withdrawal symptoms so that the transition to buprenorphine-naloxone can be completed and they can move on to a new chapter of their lives, free from the suffering and limitations imposed by opioid dependency. Accordingly, ACT treatment puts personal values first, always emphasizing the kind of life and valued activities  the patient is moving toward by taking on this challenging transition. The goal is to dignify the distress and give it purpose and meaning.Once the course has been set by clarifying personal values, the next priority is to help the patient identify, remember, and utilize his or her already-present effective strategies for getting through crises, as well as supplement the patient’s skills with helpful behavioral/psychological tools that round out his or her “coping toolbox.” To accomplish this, distress tolerance skills from dialectical behavior therapy are often useful. These skills include distraction, self-soothing, and mindful grounding techniques using sensory awareness  that can help the person to “weather the storm” without making it worse by catastrophizing. C.D. was quite insightful about this, stating that she was keen not to engage in “awfulizing” and instead to engage in meaningful behaviors, such as going for walks, caring for her animals, and spending time with loved ones.One of the most psychologically difficult aspects to bear of the transition to buprenorphine-naloxone is increased anxiety. We know that opioid withdrawal increases anxiety, and therefore it is useful to discuss with patients how to respond to this increased anxiety. Within mindfulness and acceptance-based frameworks such as ACT and DBT, we emphasize that the more one tries to suppress anxiety out of fear, the more it rebounds. In other words, fear of fear only leads to a negative cycle that becomes more and more overwhelming. We use metaphors to teach this principle . C.D. understood this immediately based on her prior experience living with pain, saying that “if you resist, it persists.” Using the ACT matrix, we highlighted the difference between “away moves”  and “toward moves” .17; however, she was not aware that it could be used for disorders of gut–brain interaction,18 such as cyclic vomiting syndrome. Indeed, although the published evidence for the Manchester gut-focused hypnotherapy protocol is primarily based on treatment of irritable bowel syndrome,19 the protocol also has been used successfully for cases of cyclic vomiting syndrome in Manchester . Accordingly, A.W. guided C.D. through a hypnotherapy exercise that induces deep relaxation targeted at the gut–brain axis. C.D. reported feeling “very, very calm” afterward. Creating a sense of psychological safety through hypnosis can reduce the likelihood of vomiting, as the brain processes many inputs, including psychological stress, perceived danger, and opioid withdrawal, which converge and summate to trigger the vomiting response. A.W. provided C.D. with a link to audio recordings she had made that could be accessed through the internet by her patients. These recordings included mindfulness and hypnotherapy exercises, which C.D. found useful and used repeatedly to help her to “ride the waves” of pain, nausea, and anxiety during this important transition. Notably, to date, A.W. and C.D. have not met in person, and all psychotherapy, mindfulness, and hypnotherapy sessions were conducted over the Ontario Telehealth Network or  by telephone.Finally, psychological intervention for C.D. involved clinical hypnosis for nausea and vomiting symptoms. C.D. was already familiar with hypnotherapy for pain reliefThree weeks have elapsed since the day when the in-person induction of buprenorphine-naloxone took place. Currently C.D.’s nausea and vomiting have stabilized, and given her sensitivity to fluctuations in opioid dose, the decision was made to stay on 16 mg of buprenorphine-naloxone for some time. We have started to introduce neuropathic pain medications for the PHN. C.D. has a long road ahead and she will continue to receive the support of the TPS team. She is coming to terms with the fact that there is no “easy” solution or quick fix to her health problem.20 Our experience with buprenorphine-naloxone for complex, chronic, opioid-dependent patients with pain is that it can provide effective pain relief while not feeding into the spiral of escalating opioid requirements typically seen with μ-opioid agonists.21 From a harm reduction perspective , the safety profile of buprenorphine-naloxone is superior to that of methadone22; hence, we selectively opt for buprenorphine-naloxone preferentially over methadone for patients struggling with opioid escalation/management in the context of a chronic persistent pain.Patients living with persistent pain and taking long-term opioids often require ever-increasing doses to maintain pain control due to opioid tolerance, while at the same time experiencing more and more side effects, including opioid-induced hyperalgesia.K.S. is a 44-year-old married male currently on disability, who was referred to the Opioid Deprescribing Program secondary to chronic opioid therapy, continued chronic pain, complex medical morbidities, and complex mental health morbidities. He attended an educational lecture on opioid deprescribing and was subsequently offered a consult. He presented for his initial consultation at the beginning of March 2020. He is supported by Assured Income for the Severely Handicapped and lives with his wife, parents, and autistic niece. He has struggled with chronic degenerative myofascial lumbar back pain, along with widespread pain, for which he was prescribed hydromorphone. He also described a right S1 radiculopathy and joint pain reported as 8–10/10 pain intensity daily on a numerical rating scale. He had been seen at the Spine Triage and Assessment Program at Foothills Medical Center where surgery was ruled out. Medical comorbidities included diabetes mellitus type 2, obstructive sleep apnea with CPAP, dyslipidemia, restless leg syndrome, and hypertension. Mental health diagnoses included a history of bipolar disorder. Nonopioid medications included moclobemide, lurasidone, pramipexole, lamotrigine, dextroamphetamine, rosuvastatin, mirabigron, semaglutide injection, diclofenac, ondansetron, gabapentin, and topical lidocaine/gabapentin/diclofenac. He is also prescribed cannabis oil in a 1:1 ratio of THC:CBD. Initial multidisciplinary assessment determined a borderline personality disorder and somatic symptom disorder, with predominant pain along with a high level of pain catastrophizing .His chronic opioid therapy included hydromorphone 8 mg q4 h (40 mg daily) and hydromorph contin 3 mg TID, a milligram morphine equivalent dose of 245 mg/day. He often ran out of his medications early, due to uncontrolled pain. There was no history of addiction and no aberrant use of his prescribed opioids, including crushing, snorting, injecting, or purchasing illicit or other prescribed opioids. At the initial visit, buprenorphine-naloxone was discussed as an alternative treatment if he was unable to taper his opioid dose and his pain could not be stabilized. A referral to interventional physiatry was also completed, but due to the COVID-19 pandemic it was put on temporary hold as the program was shut down. It was decided to start with an initial taper of 3 mg/day of his hydromoph contin dose, representing 6% of his total daily milligram morphine equivalent dose.23 K.S. decided that it would be best for him. Education was provided on a home induction protocol and a prescription was called into the pharmacy.At 4 weeks, a telemedicine call was arranged for his next appointment instead of meeting in person. At the beginning of April 2020, the clinic made the decision to eliminate face-to-face appointments to reduce risk of viral transmission. The plan was to taper another 3 mg of hydromorph contin. K.S. reported a recent fall during which he injured a knee. He complained of increased pain and reported a consequent increase in opioid use, which depleted his medication supply early. K.S. admitted that the opioids were causing distress and impairment in his life. He was using more than intended in a day, unable to cut down or stop using them, craving them, especially when he was distressed, and they were affecting his mental health. He met the criteria for opioid use disorder, moderate and was unable to taper off his medication. After education and a discussion of the possible benefits of buprenorphine-naloxone, a first-line treatment for opioid use disorder,On day 2 of the home induction, K.S. was called and reported feeling better and was stable at 18 mg of buprenorphine-naloxone. His mood had improved, his pain had significantly reduced, and he was thankful for his decision to initiate buprenorphine-naloxone. A follow-up via telephone was done 1 week later when K.S. reported that his pain intensity had dropped to a 2/10 and was not causing him any distress or impairment throughout the day. He did notice some pain at the end of the day, which led to cravings, but these would go away after a couple hours without any further intervention.24 and an acceptance and values-based approach along with emotion regulation skills, as previously described, is of great importance in developing long-term and meaningful improvement in quality of life.25He subsequently met with a therapist via telemedicine within the Opioid Deprescribing Program and they reviewed cravings and triggers for him. DBT skills were reviewed with a focus on distress tolerance and a plan was implemented to continue one-on-one psychological support until he starts a DBT skills group. The goal of DBT in this context is to reduce emotional distress in order to help reduce pain and improve his ability to cope with the pain. Psychological distress and catastrophizing are known to increase pain,26; hence, developing a simplified protocol was important. In-office, monitored inductions have been the traditional way to initiate buprenorphine-naloxone treatment, but home inductions have similar efficacy and safety.27–29 In Canada there is a practice of daily witnessed dosing at the clinic or pharmacy for patients prescribed methadone or buprenorphine-naloxone, although this can lead to poorer retention to treatment and higher costs to the health care system with no known benefits31 compared to patients who are dispensed weekly/monthly medications. The use of the home induction protocol, which eliminates unnecessary face-to-face visits, is vital to reduce COVID-19 exposure and transmission in the setting of a pandemic.The home induction protocol for prescription opioids was designed to improve patient understanding and reduce patient discomfort and for educational purposes to improve physician prescribing. It is currently part of the continuing medical education for chronic pain offered by the Alberta Pain Society. One barrier to prescribing buprenorphine-naloxone involves a lack of knowledge and skill in the induction phase32 On day 1, a prescription is initiated for buprenorphine-naloxone 2 mg SL q1 h for 8 h . The patient is advised to “take 2 mg 1 tablet every hour until you start to feel better and the pain improves up to a maximum of 16 mg.” On day 2 . The travel that C.D. endured on the day of the induction  likely contributed to her visit to the emergency department, which could have been avoided.33 during COVID-19. Emergency departments are using telemedicine to triage patients with COVID-19 symptoms. In dealing with C.D.’s case, telephone, provincial telemedicine, and social media services were utilized. The Toronto General Hospital TPS clinic has already implemented a mobile health e-platform (Manage My Pain) into clinical care34 and is testing this solution. As e-health technology evolves, platforms that can enable physical examination would be preferable for new consultations. The case of K.S. makes it clear that successful home buprenorphine-naloxone inductions are feasible and likely represent a viable clinical pathway for the future given North America’s current opioid crisis.A recent manuscript highlighted some of the benefits and challenges associated with the rapid introduction of telephone and e-health pain management servicesHistory of trauma/current PTSD. In our clinical experience, patients with a history of trauma are more likely to have difficulty with opioid withdrawal and the transition to buprenorphine-naloxone. The increased panic and anxiety during this time requires additional skills training to successfully tolerate and move beyond this transition; however, with support, patients can reach their treatment goals.History of suicidal ideation and behavior. Patients in withdrawal from opioids may experience dysphoria. In patients with a history of suicidal behavior, a suicidal crisis can be triggered. Clinicians should screen in advance for this history , monitor closely, and offer additional supports if needed. With psychological support, patients with this history can successfully transition to buprenorphine-suboxone.daily (not intermittent anxiolytic use but daily high-dose use) are more likely to have difficulty with the buprenorphine-naloxone transition. Acceptance and commitment therapy35 or motivational interviewing36 prior to attempting buprenorphine-naloxone induction may be of help in increasing motivation to tolerance distress, as well as skill development in acceptance of aversive sensations and distress tolerance for emotions.21Daily anxiolytic use. In our clinical experience, patients who are using both opioids and anxiolytics Patient education is paramount. Patients routinely receive educational information about the induction process, including a “road map” of the steps involved see  and fran37 and that enrollment in the program is voluntary. The session reviews evidence and introduces the patients to the interdisciplinary team, including psychology, nursing, nurse practitioners, administration, and physicians. A small section includes the possibility of buprenorphine-naloxone for some patients, specifically those with addiction or suspected opioid-induced hyperalgesia39 and/or opioid antinociceptive tolerance.4041 Having skilled therapists with training in DBT has been extremely helpful in improving psychological distress and hence pain outcomes. Often patients with high distress and high anxiety require significant reassurance, validation, and education prior to the buprenorphine-naloxone induction, similar to patients with a history of trauma/PTSD.About 30% of patients presenting to tertiary chronic pain programs have a comorbidity of borderline personality disorder, leading to higher complexity for both the treatment of their pain and mental health.Education is key. Handouts and confirmation of the protocol and possible side effects are key. A video, forthcoming from Alberta Health Services, Addiction and Mental Health, will add extra education as well. The patient should be advised of proper administration of the medication. Phone calls on day 2 are extremely important to determine dose and alleviate anxiety.Often, a difficulty in tolerating the medication stems from ingestion of the medication orally, instead of letting the medication be absorbed sublingually. This can lead to gastrointestinal upset, nausea, and vomiting. Larger tablets  will take longer to dissolve (up to 10–15 min). If any portion of the tablet is orally ingested, the patient will have a higher chance of experiencing gastrointestingal side effects. When this is suspected, it may also be advised for the patient to rinse his or her mouth after dissolving the medication rather than swallowing the saliva, thereby minimizing oral ingestion.It is important to discuss the risk of precipitated withdrawal with the patient, along with proper management of it. Precipitated withdrawal occurs when the patient starts buprenorphine-naloxone before sufficient opioid withdrawal is reached . The patient is thus advised to wait for the symptoms of precipitated withdrawal, which often presents as a rapid rise in withdrawal symptoms, to settle and for natural opioid withdrawal to occur, prior to continuing induction. This may take 3 to 4 h. Withdrawal symptoms may be alleviated during the process with the judicial use of medications such as clonidine and gabapentin.All patients who are enrolled in the program undergo an education session prior to their first appointment. This is important in discussing the role of opioid deprescribing to discontinuation and improvements in painC.D. and K.S. both highlight complex chronic pain and opioid use disorder cases that were facilitated via telemedicine during the COVID-19 pandemic. In the case of C.D. it was an abrupt transition that, without the remote capabilities being given to the team to engage patients, may have ended with greater distress. The case of K.S. illustrates that with proper instructions by the team in advance of starting buprenorphine-naloxone, a home buprenorphine induction of a patient on high-dose opioids can be managed safely by the patient in the comfort of his or her own home. Telemedicine has been thrust to the forefront of health care in the past month. Based on our positive interactions with the team and patients and the ability to bring the team together to solve complex situations at the drop of a hat, it is hard to imagine returning to health care without the ability to remotely assess and interact with our patients post-COVID-19.


The use of opioid analgesia is common in both the acute and extended post-operative periods after rotator cuff repair. The current opioid crisis has prompted surgeons to seek alternatives that minimize or even eliminate the need for oral opioids after surgery.We sought to investigate the effects on post-operative opioid use of a surgeon-administered block of the suprascapular and axillary nerves in arthroscopic rotator cuff repair (ARCR), in particular to quantify outpatient opioid consumption and duration.In this prospective observational study, all patients undergoing primary ARCR performed under general anesthesia by a single surgeon were studied over a 15-month period. Of 91 ARCRs performed, 87 patients were enrolled and followed prospectively. At the conclusion of the procedure, the surgeon performed “local–regional” nerve blockade with injections to the sensory branches of the suprascapular nerve and the axillary nerve, as well as local infiltration about the shoulder. Use of medications in the post-anesthesia care unit was left up to the anesthesiologist. Patients were prescribed oral opioids (hydrocodone/acetaminophen 5/325 mg) for analgesia after discharge. The quantity and duration of opioid use and pain scores were recorded for 4 months. Statistical analysis was performed to evaluate factors that could account for greater opioid use.Total opioid consumption ranged from 0 to 30 opioid tablets  over the 4-month period. Post-operatively, 91% of patients took between ten or fewer tablets, and 39% took no opioids. The average duration of opioid use was 2.4 days. No patients were taking opioids at the 4- to 6-week or 4-month follow-up visits, none required refills, and none received prescriptions from outside prescribers. No statistically significant differences were seen in opioids taken or duration of use in regard to tear size, sex, body mass index, surgery location, or procedure time. There was a significant inverse correlation between opioid use and age. In addition, the cost of the surgeon-performed procedure was substantially lower than that associated with pre-operative nerve blockade performed by an anesthesiologist. All patients were satisfied with the post-operative pain management protocol. Average reported post-operative pain scores were low and decreased at each visit.With this local–regional nerve-blocking protocol, opioid use after ARCR was unexpectedly low, and a large proportion of patients recovered without any post-surgical opioids. The correlation seen between opioid use and age may not be clinically significant, given the low use of post-operative opioids overall. These results may be useful in guiding post-operative opioid prescribing after ARCR, as well as in lowering costs associated with ARCR.The online version of this article (10.1007/s11420-019-09745-4) contains supplementary material, which is available to authorized users. Outpatient arthroscopic rotator cuff repair (ARCR) is a common procedure, but it has been associated with significant post-operative pain , 24. EffThere has been a call for evidence-based guidelines for prescribing opioids after orthopedic surgery . StudiesSurgeons are searching for ways to improve opioid stewardship without compromising effective analgesia for ARCR. Regional nerve blocks are widely used in ARCR to control acute surgical pain . InterscIn 2019, we published a study in this journal on the effects of surgeon-administered local and regional blockade  of specific genicular nerves on post-operative analgesia after anterior cruciate ligament reconstruction (ACLR); we quantified outpatient opioid consumption and duration through the complete post-operative course . We founThe purposes of the current study were similar: to investigate the efficacy of a surgeon-administered local–regional block of specific nerves on post-operative analgesia after ARCR in opioid-naïve patients and to quantify the outpatient opioid consumption and duration throughout the post-operative course. We hypothesized that a new protocol of surgeon-administered local–regional anesthetic to the suprascapular and axillary nerves could provide desirable blockade with sufficient post-operative pain control while lowering post-operative oral opioid requirements. We also aimed to answer questions about long-term (at 4 months) opioid requirements after ARCR and differences in opioid requirements that may be associated with surgical and patient variables.The methods used in this study were similar to those reported in our study of post-operative opioid use after ACLR . InstituAll procedures were performed on an outpatient basis using standardized operative and post-operative treatment protocols. Procedures were performed at two facilities , each with its own anesthesia group. According to practice protocol at both facilities, prescription of intra-operative medications was left to the discretion of the individual anesthesiologists. The patients were placed in the beach chair position after induction of general anesthesia. No pre-operative blocks were performed. All surgical procedures were completed using a standardized protocol by the study’s surgeon. An arthroscopic suture-bridge technique was used to repair the rotator cuff. This double-row technique involves the creation of a medial and a lateral row of bioabsorbable anchors (4.75 mm in diameter). The cuff was mobilized for a direct repair to the tuberosity; no margin convergence was used. The remaining parts of the procedure  were then performed as necessitated by the associated pathology. The intra-operative medications provided were also at the discretion of the anesthesiologist and were not recorded.The nerve blocks were administered at the conclusion of the procedure, in the operative suite with the patient still under general anesthesia. The injections were performed by the surgeon with the aim of providing anesthetic blocks to the sensory branches of the suprascapular nerve and axillary nerve, as well as local infiltration about the shoulder. We termed this a “local–regional block” of the shoulder. We used no ultrasound or neurostimulation to guide administration of the local–regional block. The local anesthetic infiltration included a total of 60 cc of 0.25% bupivacaine (not to exceed 2 mg/kg) using a 22-gauge needle.The approach to the suprascapular nerve was based on superficial anatomic landmarks and similar to that described by Matsumoto et al. . The skiANB was then performed. Our approach was similar to the method described by Park et al. . PosteriAfter wound closure, the dressing and sling with abduction pillow were applied in the operating room, and the patient was transferred to the post-anesthesia care unit (PACU). Patients were given ice packs and encouraged to use them frequently. Additional pain medication was administered through the intramuscular, intravenous, or oral route according to the patient’s pain level and the anesthesiologist’s discretion. Although the medications and dosages used varied between anesthesia groups, adjunctive medication was limited to short-acting opioids, acetaminophen, and NSAIDs. No long-acting medication, ketamine, or gabapentin was administered. Additional pain pumps, nerve blocks, and patient-controlled analgesia (PCA) were not used. Surgical time, PACU hold time, and facility were recorded for future comparison.In accordance with our usual practice, patients were discharged with a prescription for 30 tablets of hydrocodone/acetaminophen 5/325 mg  . All patPost-operatively, all patients were seen by the surgeon or physician assistant (PA) in the office the day after surgery, on post-operative day 7, at 4 to 6 weeks, and at 4 months. Patients were seen more frequently if it was deemed clinically necessary. Patients had a dressing change on day 1 and were allowed to shower that evening. Post-operative therapy, using a standardized protocol, began within 7 days after surgery, focusing on a return of full range of motion (ROM) and restoration of strength. Use of the sling was discontinued at 6 weeks. Physical exams at 4 to 6 weeks and at 4 months included documentation of any sensory deficit over the shoulder or perceived suprascapular or axillary nerve dysfunction on manual muscle testing.The primary study outcome measure was post-discharge use of opioid pain medication. The quantity of opioid use (number of a hydrocodone/acetaminophen 5/325 mg tablets [± standard deviation]) and duration of opioid use (latest post-operative day on which they were taken) were documented at each visit. In addition, any prescription refill requests and visual analog scale (VAS) pain scores were recorded. Patients were specifically asked during the first two visits about rebound pain crisis. This was defined as a significant pain event causing personal distress, phone call to a physician, or evaluation at an emergency department. Patients’ satisfaction with our post-operative pain management protocol was assessed using a Likert scale at the third post-operative visit. Satisfaction was rated 1 to 5, with 1 being strongly dissatisfied and 5 being strongly satisfied.Patients reported their opioid use  at each visit, having completed self-administered at-home pill counts. Data were entered into the patient’s electronic medical record and a spreadsheet. All patients were prescribed the same post-operative dosage of opioids. The dosage was also converted to OMEs to facilitate later comparisons with other studies. At the 6-week and 4-month visits, we accessed the Florida Prescription Drug Monitoring Program  database to determine whether any opioids had been prescribed by other physicians.U test for categorical variables, and Spearman ρ correlations for continuous variables. For categorical variables with more than two groups, we initially ran a Kruskal–Wallis analysis of variance. For variables with between-group values with a p value lower than 0.1, subgroups were evaluated pairwise using the Mann–Whitney U test. For all variables, p < 0.05 was considered to be statistically significant.Each patient’s rotator cuff tear was measured intra-operatively and assigned to one of three categories according to the size of the tear: small (0 to 1 cm), medium (1 to 2 cm), or large (> 2 cm). Statistical analysis and graph creation were accomplished using Excel software . We performed statistical analysis of demographic and clinical factors that could contribute to greater opioid consumption or increased duration of use. Because of the nonparametric nature of our data, we used the Mann–Whitney Complete data were available for all patients. Table p = 0.043; Table p = 0.071). No significant differences were seen in opioid consumption or duration of use with the remaining variables (Table Patients were divided into four age groups for comparison Table . There wAverage patient-reported pain scores on the 10-point VAS were low (≤ 3) for all post-operative visits . The cost of the local–regional technique was approximately $12 (for 60 cc of bupivacaine) and generally took an additional 2 min for the surgeon to administer after surgery.The principal findings of this study are comparable with those shown in our 2019 study of opioid use after ACLR : pain coOne limitation of our study is reliance on patient reporting of opioid use. However, we did use our state’s prescription drug monitoring program (E-FORCSE) to ascertain whether patients were receiving opioids from outside providers. Another limitation is that we did not track patients’ ibuprofen use. The main objective was to document home opioid use. Because ibuprofen is so readily available in most homes, we felt that it could not be reliably accounted for, either in patient-reported use or in prescription monitoring. We also did not track the medications administered by the anesthesiologist in the immediate post-operative period. Controlled studies may be able to eliminate any possible discrepancies in regard to this.In addition, we did not specifically quantify functional outcomes. Patients’ strength, range of motion, and satisfaction were assessed and met or exceeded the expectations of both patients and the senior author (G.L.C.). Large population-controlled studies may also help to further analyze the relationship between age and post-surgical opioid use. Orthopedists have been called upon to limit outpatient prescriptions of opioids to minimize misuse and diversion. This therefore was our focus, while documenting the 4-month post-operative period. It has been shown that pre-operative opioid use is a risk factor for increased post-operative use . HoweverThe high degree and duration of post-operative pain associated with ARCR make it an ideal testing ground for alternative anesthetic protocols in shoulder surgery. One major challenge is adequately controlling pain while avoiding the risks of excessive opioid use, such as misuse, abuse, and diversion , 21. ISBA different strategy would be to focus on the distal nerves that innervate the shoulder. The suprascapular nerve is estimated to innervate 70% of the joint, capsule, subacromial space, and acromioclavicular joint . ImportaAn ideal regional anesthetic for outpatient ARCR would be a blockade that is technically simple, has a rapid onset of action, is highly effective, has no or few adverse effects, and is relatively inexpensive. In general, anesthesiologist charges at our institutions for ISB, SSNB, or ANB are approximately $1500. In contrast, the cost of our block technique was $12 and took 2 min to perform. What differentiates this technique from others is that the surgeon uses anatomic landmarks, without ultrasound or electrodiagnostic guidance, and performs it at the conclusion of surgery, while the patient is still under general anesthesia. This strategically minimizes patient inconvenience, costs, and procedure time. Importantly, it also eliminated the need for additional PCA or anesthetic blocks. Home care after discharge was simple, with no infusion devices to manage. There were no readmissions or occurrences of significant rebound pain crisis after discharge, nor were there any late night calls to the physician or emergency center evaluations for pain. In addition, we found no suprascapular or axillary nerve deficits on physical exam during follow-up.Pre-operative education may help to reduce opioid consumption. In one study, patients given a pre-operative video and handout detailing the risks of opioid overuse had a reduction from an average of 1308 to 768 OMEs for the first 3 months after ARCR . Our preA survey study of a large group of experts in shoulder surgery found that they initially prescribed an average of 462.5 OMEs  to patients after ARCR . In addiA study by Shah et al. demonstrated that chronic opioid use can occur after just 3 days of medication . Leroux In conclusion, opioid use was unexpectedly low in patients undergoing ARCR after a surgeon-administered nerve block and infiltration. With this protocol, a large proportion of patients can recover from ARCR without opioids. Our results could be useful in guiding post-operative opioid prescribing after ARCR and in lowering anesthesia costs associated with ARCR.ESM 1(PDF 516 kb)ESM 2(PDF 1224 kb)


Dear Editor:We appreciate the valuable comments on our submitted article  providedIn our hospital, we routinely provide a postoperative analgesic measure for a patient who underwent RALP. Patients can choose between ITMB with IV-PCA, RSB with IV-PCA, and IV-PCA only. Informed consent was obtained after detailed information about the advantages and disadvantages of each measure was discussed. Each analgesic protocol was administered to approximately 30% of patients, a finding that may be related to the distribution of the study population into three groups of 30 patients. Because we wanted to make sure that ITMB was superior to other pain control methods performed in our institution, we designed our study to investigate the severity of postoperative pain, as a primary outcome, according to the pain-relief methods. There is a risk of respiratory depression with ITMB. We are always concerned about this potentially life-threatening risk. This is the reason why we began the current study. We wanted to find out if RSB with IV-PCA has a comparable pain control efficacy to ITMB with IV-PCA.The patients undergoing prostate surgery in our study, including RALP, were elderly (median [IQR] age = 65 62–71] years) [ years) [n = 10) and those who received ITMB (n = 10) were 47.1 and 29.1 mL, respectively. The standard deviation (SD) among the 20 patients was 23.6 mL. Therefore, a minimum sample size of 27 patients/group was required to afford an α value of 0.05 and a power of 0.8. We recruited 30 patients for each group assuming a dropout rate of 10%  [The minimum sample size was based on the difference in cumulative IV-PCA drug consumption on POD 1 between patients who received RSB and those who received ITMB, calculated using preliminary and retrospective data from electronic medical records. Mean cumulative IV-PCA drug consumption on POD 1 by patients who received RSB (Our study was limited in that patients were not randomly allocated, despite the use of comparable groups. A randomized setting was considered but rejected due to ethical concerns that IV-PCA alone may provide insufficient pain relief compared with the other two analgesic regimens. Therefore, it was not possible to determine whether the analgesic results were solely related to the pain relief regimens. However, our study suggests that ITMB, as an analgesic protocol that targets both parietal and visceral pain, may contribute superior pain relief and better patient perception in terms of early postoperative recovery following RALP, which is a more advanced and less invasive surgical technique. Additional randomized studies are required to validate our analgesic results in the field of RALP.


Musculoskeletal pain is often caused by injury to the bones, muscles, tendons, ligaments or nerves. Symptoms can be localized or generalized. Mild-moderate symptoms are treated with topical/oral over the counter drugs. Microemulsion delivery formulations are thermodynamically stable, have superior bioavailability and better penetration of lipophilic and hydrophilic drug into the dermis. A prospective observational study in patients: 18 years or older, with mild-moderate musculoskeletal pain; with severe pain without adequate pain control; with severe pain and could not tolerate oral agents; with renal impairment were invited to try diclofenac 2% in microemulsion foam. They were followed up at 2 and 4 weeks. A 50% reduction on a visual analog pain scale was considered success. Adverse events were defined as irritation, gastrointestinal upset/bleed, rectal bleed, and hematemesis. The objective was to determine the efficacy and toxicity of diclofenac 2% in microemulsion foam.Thirteen consecutive patients with musculoskeletal pain consented to participate. Two patients were lost to follow up. Two of the 11 patients reported minimal improvement, while nine patients reported minimum 50% reduction. No adverse effects were reported. Diclofenac 2% in microemulsion foam is effective in the treatment of mild to moderate musculoskeletal pain and well tolerated. It is recommended that a total dose should not exceed 320 mg of diclofenac per day [Musculoskeletal pain is often caused by an injury to the bones, muscles, tendons, ligaments or nerves. The symptoms can be localized or generalized. The mild to moderate symptoms are usually treated with acetaminophen, or non-steroidal anti-inflammatory drugs (NSAID) such as ibuprofen . Current per day .®) [Compounding pharmacies can provide various prescription strengths of diclofenac in pluronic lecithin organogel (PLO). The most common strengths prescribed are 5–10% in PLO gel to be applied once daily or twice daily. Because the PLO gel is poorly absorbed, a higher dose is required to relieve pain. However, topical NSAID is not without side effects. GI bleed has been observed in clinical trials using the 1.5% diclofenac (Pennsaid®) .Concerns were raised by many clinicians about the use of high concentrations of topical diclofenac being used. We explored the possibility of developing a better delivery compound that would require less active drug and provide better or equivalent efficacy. As a result, a microemulsion compound (foam) was developed as a delivery system. In vitro, it has been shown to increase absorption through the dermis when compared to the currently available products . This woPatients 18 years or older, with mild to moderate musculoskeletal pain. Mild to moderate pain was defined as a patient reported pain with a visual analog pain score ≤ 6 out of 10Patients with severe pain who, despite using other treatment agents such as opioid, acetaminophen or cortisone injection, who still did not receive adequate pain control; orPatients with severe pain who could not tolerate oral NSAID or;Patients with renal impairment in whom oral NSAID use is contraindicatedThis is a prospective observational study at a family medicine clinic. All consecutive eligible consenting patients with mild to moderate musculoskeletal pain of a variety of durations were treated with topical 2% diclofenac in microemulsion foam applied as a topical spray. The Northern Alberta Academic Family Physician Fund, a fund intended to support initiatives promoting the advancement of family medicine, provided 3000 Canadian dollars to purchase the active ingredients for the study. The study aimed to recruit 15 patients. The eligibility criteria were as follows:Patients who have hypersensitivity to diclofenac; orPatients with open wounds or infection at the application site; orPatients under 18 years of age; orWomen who are pregnant; orPatients with more than 1 active painful site.Exclusion criteria include:All patients were provided with two 50 mL bottles of 2% diclofenac in microemulsion foam to be applied twice a day and allowing up to seven applications for each site a day. Each 50 mL bottle contained 1 g of diclofenac in microemulsion solution. Each application contained about 1 mL which is enough in each bottle for 50 applications in the 1-week Patients were followed up in 2 weeks. Pain control was assessed at the follow up visit. If there was patient reported improvement on the VAS, another two bottles were provided and the patients were followed up again in 2 weeks. Improvement is defined as ≥ 50% reduction on visual analog pain scale after 2 weeks. Adverse events were defined as irritation at the application site, gastrointestinal (GI) upset, GI bleed, rectal bleed, vomiting blood, and rash. Verbal comments from the patients about the experience of using the 2% diclofenac in microemulsion foam were also collected and documented at each visit.The observational study received Research and Ethics approval (Pro00079011) from the University of Alberta. Patients with musculoskeletal pain were identified during their regular visits to the family physician. Patients who needed a change in therapy and met the inclusion criteria were offered the new preparation. They were informed by their clinician about our wish to monitor the effects of this standard medication offered in a new format and written informed consent was obtained from eligible patients for monitoring of the effects. In the first 2 weeks, 13 patients met the eligibility criteria and provided signed consent. Two patients were lost to follow up in 2 weeks. Of the remaining 11 remaining patients, nine patients noted significant improvement in pain control. Some of them requested prescriptions for the 2% diclofenac in microemulsion foam for their family members who were also suffering from musculoskeletal pain. Since, at that time, there was a limited supply of the 2% diclofenac in microemulsion foam for the study, the investigators decided to discontinue enrolling patients. The study patients were given two more bottles of the 2% diclofenac in microemulsion foam for the following 2 weeks. The treatment was extended to use by other patients and physicians by prescription since all constituents are approved therapeutically. At this time other family physicians could provide a prescription to their patients.Table Topical NSAIDs are used as an alternative to oral NSAID for mild to moderate musculoskeletal pain to provide localized drug delivery with equal efficacy but minimizing systemic adverse effects. The maximum recommended daily dose should not exceed 320 mg of diclofenac per site . For lowIn Canada, pharmacies are permitted to provide non-commercially available concentrations of diclofenac in any semisolid base. The common prescription concentrations are compounded in PLO as semisolid base. There is limited published information about the efficacy or toxicity of diclofenac in PLO gel , 8. One Microemulsion transdermal drug delivery formulations are thermodynamically stable, and have superior bioavailability and better penetration of lipophilic and hydrophilic drug into the dermis , 10. A s® without adequate relief. All of these patients, however, reported at least 50% reduction in the visual analogue score from baseline after using diclofenac 2% in microemulsion foam. Patient number 5 reported no response to the diclofenac microemulsion foam. His pain severity could be associated with the patient’s severe back pain which was not treated. Patients number 1 and 11 with severe pain were given the topical formulation because they both have renal insufficiency and they would be at risk of renal function deterioration if given oral NSAID. Patient number 2 was awaiting knee replacement surgery and preferred not to take oral NSAID.This is the first observational study to assess the clinical effects and adverse events using diclofenac powder in microemulsion in the treatment of musculoskeletal pain. Due to the small sample size, the before and after pain intensity statistical tests could not be used to provide meaningful results. Prior to enrolling in the study, five of the 11 patients had used either diclofenac 10% in PLO gel or diclofenac 1.5% or 2.32% alcohol based or EmulgelMost notable comments from the patients were that the microemulsion foam is less messy than PLO gel and the absorption was almost instantaneous which resulted in quicker onset of action. No adverse event was reported by the patients in the study.Diclofenac 2% in microemulsion foam appears to be effective in the treatment of mild to moderate musculoskeletal pain either as a single agent or an adjuvant agent. It was well tolerated.This is an observational study and the sample size is small. Although a majority of patients had positive response, a higher strength was trialed on the two patients who reported inadequate response.


Despite promising preliminary results of transcranial direct current stimulation (tDCS) treatment in patients with fibromyalgia (FM), several issues need to be addressed, including its limited efficacy, low response rate, and poor tolerability. We investigated the efficacy and safety of tDCS as an add-on treatment for chronic pain in Korean patients with FM. This study enrolled 46 patients who were refractory to pain medications from May 2016 to February 2017. A conventional tDCS device was used to supply 2 mA of current for 20 min on five consecutive days. The primary end-point was a change in visual analogue scale (VAS) pain score at the end of treatment; secondary end-points included changes in Fibromyalgia Impact Questionnaire (FIQ), Brief Pain Inventory (BPI), Brief Fatigue Inventory (BFI), Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and Medical Outcomes Study Sleep Scale (MOS-SS) scores. After tDCS, 46 patients showed clinical improvements in VAS pain scores on days 6, 13, and 36 compared with day 0 (p < 0.001). Improvement in FIQ was seen on day 13. The BDI decreased significantly on days 6 and 36, and BFI improved significantly on days 6 and 13. There were no significant improvements in STAI-I, STAI-II, and MOS-SS scores after tDCS. No serious adverse events were observed. Our results suggest that tDCS can result in significant pain relief in FM patients and may be an effective add-on treatment. In addition, dysregulated neurotransmitters in FM patients can result in exaggerated central sensitization to pain5.Fibromyalgia (FM) is a chronic pain disorder characterized by widespread pain and associated symptoms such as emotional distress, fatigue, and sleep disturbances. Although the pathophysiology of FM remains unclear, it is believed to be associated with changes in pain and sensory processing in the central nervous system, especially nociceptive pathways. These changes may be caused by maladaptive plasticity in pain-associated neural circuits6. Other studies9 also showed that tDCS could induce pain reduction and maintain an improved pain status in FM patients. However, a Cochrane review10 noted that tDCS leads to small, short-term reductions in pain, and these effects are not likely important clinically and were effective in only a small number of FM participants. The number of published clinical trials was small and most of the trials had small sample sizes and short follow-up durations12. In addition, previous trials are biased by a lack of adequate blinding. Taken together, the evidence in support of tDCS remains insufficient. In addition to its efficacy toward pain intensity, little is known about the effect of tDCS on associated symptoms, such as fatigue and depression. No study has explored the booster effect of tDCS in FM patients who initially responded to tDCS to maintain the treatment effects. Because the effect sizes for pharmacological treatment are generally small, it is necessary to investigate whether tDCS is effective in patients who are refractory to pain medication. Thus, we explored the efficacy, tolerability, and safety of tDCS treatment as an add-on treatment for chronic widespread pain in a large number of Korean patients with FM.Based on the mechanism described above, recent studies have shown that noninvasive brain stimulation techniques may be beneficial for chronic pain syndromes, including FM. Among the brain stimulation techniques, transcranial direct current stimulation (tDCS) is a novel treatment in FM patients with chronic pain. A previous randomized controlled trial by Fregni et al. reported the beneficial effect of tDCS treatment13. The inclusion criteria were as follows: (1) Pain refractory to common analgesics and medications, (2) presenting pain Visual Analogue Scale (VAS) ≥ 5, (3) revised Fibromyalgia Impact Questionnaire (FIQ) ≥ 50, (4) underwent brain magnetic resonance imaging (MRI) within 1 year, and (5) signed informed consents after appropriate explanation from a practicing physician. Exclusion criteria were as follows: (1) patients who had severe psychological disorders, (2) brain disease such as epilepsy, stroke, traumatic injury, or tumor, (3) history of brain surgery, (4) intracranial implant or appendages, (5) developmental disorder, (6) drug abuse, and (7) pregnancy. A total of 46 participants were enrolled in this study. Patients were medicated with the same dosage of their prescribed medication at the time of enrollment and during the study period. All enrolled patients provided written informed consent at the time of enrollment in this study. This study was approved by the Institutional Review Board/Ethics Committee of Chonnam National University Hospital  and was registered with the Korean National Clinical Research Information Service . This study was conducted in accordance with the Declaration of Helsinki and the Good Clinical Practice guidelines.We enrolled FM patients who were diagnosed and treated in the Department of Rheumatology at Chonnam National University Hospital in Korea from July 2016 to February 2017. All patients satisfied the 2010 American College of Rheumatology (ACR) criteria of FMThis study lasted 6 weeks including a 1-week screening phase, a 1-week tDCS treatment phase, and a 4-week follow-up observation phase in each patient. To investigate the efficacy of tDCS treatment, we assessed pain VAS scores and associated symptoms using several parameters. We assessed the pain VAS score on day 0 , days 1–5 (during treatment), day 6 (1 day after treatment), day 13 (treatment after 1 week), and day 36 (treatment after 1 month). Other parameters, including revised FIQ, brief pain inventory (BPI), Beck Depression Inventory (BDI), brief fatigue inventory (BFI), state-trait anxiety inventory (STAI), and the medical outcomes study sleep scale (MOS-SS), were assessed on days 0 , 6, 13, and 36 (post-treatment).All patients were scheduled to receive tDCS treatment in five daily sessions  for five consecutive days. Conventional tDCS devices were connected to multichannel stimulation adaptors and 2-mA intensities of current were applied across the anode and cathode for 20 min. The anode electrode was placed over the M1 cortex (using the 10/20 system of electrode placement) and the cathode electrode was placed over the contralateral M1 cortex area. After applying gel on the sponges covering the anode and cathode, the physician positioned electrodes on the correct areas. The physician then placed a net-like hat on the patient’s head for immobilization.The primary efficacy outcome was the change in pain VAS score from baseline (day 0) to treatment after 1 week (day 13). The pain VAS consists of a scale ranging from 0 (complete absence of pain) to 10 (corresponding to worst imaginable pain).Secondary efficacy outcomes included revised FIQ, BPI, BDI, BFI, STAI, and MOS-SS: We evaluated changes in parameters from baseline (day 0) to 1 day after treatment (day 6), 1 week after treatment (day 13), and 1 month after treatment (day 36).14. The revised FIQ has 21 questions based on an 11-point numeric rating scale from 0 to 10, with 10 being worst. All questions were framed in the context of the past 7 days. The revised FIQ was divided into three linked sets of domains including function (9 questions), overall impact (2 questions), and symptoms (10 questions). The summed score for function (range 0–90) was divided by 3, the summed score for overall impact (0–20) was not changed, and the summed score for symptoms (0–100) was divided by 2. The total score is the sum of the three modified domain scores.The quality of life and other domains of FM were measured using the Korean version of the revised FIQ15. The BDI consisted of 21 multiple-choice questions; each item was rated on a four-point intensity scale and scores were added to give a total range from 0 to 63; higher scores represent more severe depression. To evaluate the presence and severity of anxiety, we used the Korean version of STAI16. This instrument, which consists of the STAI-I (anxiety concerning a specific event) and STAI-II , has 40 items (20 items each in STAI-I and STAI-II).To evaluate psychiatric symptoms, we measured depression using the Korean version of BDI17.The BPI is an instrument for evaluating pain that can measure the intensity of pain and the interference of pain with the patient’s life. Since pain can be variable throughout the day, the BPI asks patients to rate their pain intensity at the time of responding to the questionnaire (now) and at its worst, lowest, and average levels over the previous week. The rating can also be made for the last 24 h depending on the study design. The BPI also asks patients to rate how their pain interferes with their general activity, mood, walking, work, sleep, relationships, and enjoyment of life. We used the validated Korean version of the BPI18. The BFI consists of nine items on a single page. Fatigue and its interference are measured on numeric scales from 0 to 10. There are three items asking subjects to describe their fatigue now, at its usual level, and at its worst level during the previous 24 h using the measures “no fatigue” and “fatigue as bad as you can imagine.” The following six items describe how fatigue has interfered with aspects of their life during the previous 24 h. These items include general activity, mood, walking ability, normal work, relationships with others, and enjoyment of life. These interference scales range from 0 to 10. The global score for the BFI is calculated as the mean value of these nine items.We measured fatigue severity using the Korean version of BFI19. The MOS-SS includes 12 items categorized into six dimensions assessing sleep disturbance, sleep adequacy, somnolence, quantity of sleep/optimal sleep, snoring, and awakening short of breath or with a headache.Sleep quality was measured using the MOS-SSSafety outcomes were evaluated based on the presence and incidence of adverse events during the study. We monitored adverse events by interviewing patients after each session of tDCS and during the follow-up period using a check-list including dizziness, headache, sleep disturbance, skin reactions, etc.p value < 0.05 was considered significant.Statistical analyses were performed using SPSS for Windows software package . To evaluate the effects of tDCS, paired t-tests were used to compare mean changes from baseline with various time points after treatment. The comparisons were performed using Bonferroni adjustments. A A total of 46 patients with FM were enrolled in the present study and their baseline demographic and clinical characteristics were described in Table p < 0.001), which was maintained on day 13 (treatment after 1 week)  and day 36 (treatment after 1 month) . In addition, there was significant reduction on day 13  compared with day 0 in FIQ. However, these decreases were not maintained at day 36.The primary endpoint of our study was VAS score on day 13 (treatment after 1 week). In the present study, the pain VAS score decreased significantly on day 6 , which was also observed on day 13  and day 36 . BFI decreased on day 6  compared with day 0. The improvement in these indices was observed on day 13. BDI also decreased significantly on day 6 , which was maintained until day 36 . However, there was no significant improvement in STAI-I, STAI-II, and MOS-SS after tDCS on days 6, 13, and 36  and day 13  compared with patients with pain VAS scores less than 8. However, there was no significant difference in pain VAS score between the two groups on day 36. In addition, patients with pain VAS scores greater than 8 showed a greater decrease in BFI on day 6  compared with those having pain VAS scores less than 8. However, there was no significant difference in FIQ, BPI, BDI, STAI-I, STAI-II, and MOS-SS between the two groups , light headache (3 patients), and transient sleep disturbance (2 patients). However, there was no patient dropout or serious adverse event to prevent tDCS.We observed a significant improvement in pain, quality of life, and fatigue in patients with FM after five daily sessions of tDCS, and the adverse effects of tDCS were minor and well tolerated.8 exploring tDCS found significant pain reduction in FM patients. Those studies reported that the active tDCS group had a higher response rate and significant pain decrease compared with the sham group. Several issues were identified based on a recent meta-analysis and systematic review of tDCS12. Previous results have shown heterogeneity in the efficacy of trials at reducing pain after tDCS treatment in FM patients. In addition, most trials had a high risk of bias due to inadequate blinding. Although our study did not overcome these shortcomings of non-drug treatment due to the nature of the study, the merits of this study over the previous studies need to be discussed. First, we recruited more participants than the previous studies to get sufficient power for generalization. In addition, because it is impractical to blind the participants in the setting of such trials, we focused on the effect of tDCS in patients who were refractory to conventional treatment as an add-on treatment. In this study, the pain VAS scores after tDCS significantly decreased compared with pre-treatment. Thus, although randomized trials are needed to determine the true efficacy of the treatment, tDCS may be used in FM patients refractory to conventional treatment or in patients who cannot take medications.This study showed that pain VAS scores improved significantly after tDCS treatment. Preliminary results of early studies20. Moreover, other studies showed that tDCS may affect excitability by modulating the resting membrane potential based on fMRI data during and after stimulation. Based on fMRI data from 12 patients with FM, repetitive M1 tDCS stimulation can change the functional connectivity of regions under the electrode and structurally connected regions such as the thalamus22. According to this mechanism, it is possible that changes in functional connectivity between the thalamus and brain regions are involved in pain perception. Thus, tDCS may affect the level of neurotransmitters and change the functional connectivity of the stimulated region.The mechanism through which tDCS treatment has an effect remains unclear. Based on functional magnetic resonance imaging (fMRI), an increased level of γ-aminobutyric acid (GABA) in the anterior insula and decreased levels of glutamate and glutamine (Glx) in the anterior cingulate were found in FM patients following tDCS treatment compared with baseline24 that have used pain VAS scores as an outcome measure in the study of FM have classified severe pain as a score above 7.5. Because we assessed it in integer units, we chose a cutoff value of 8. Because no study has compared FM patients based on pain severity, it is notable that tDCS appears to have favorable analgesic effects in FM patients and is more effective in patients with severe pain.We divided the FM patients into two groups according to pain severity, and patients with more severe pain showed a greater decrease in pain VAS scores than those with less pain after tDCS treatment. Previous studies6 showed that the tDCS effect in reducing pain severity did not persist for several weeks after treatment. In addition, Valle et al.7 showed that tDCS resulted in decreased pain that lasted up to 2 months after the stimulation. The favorable effect of one session of tDCS stimulation was not maintained until the end of the follow-up period in previous trials. On the other hand, we performed booster tDCS treatment in 16 patients. Booster tDCS was effective in all patients, and these patients were not prescribed additional medication or increased doses of conventional treatment during the booster treatment. Based on the above results, booster tDCS may be used for pain exacerbations in FM patients who had initially responded to tDCS.We observed a significant pain reduction in tDCS during and after treatment, but the effect of tDCS did not persist to 1 month. In most trials, the effect after tDCS was not explicitly mentioned, and if reported, the duration of the effect was variable. Fregni et al.9, all tDCS studies in which FIQ was assessed as a measure of functional disability showed transient improvement after follow-up. This finding is consistent with our study, which also showed short-lived improvement in FIQ. Nevertheless, when we compared the slope of pain VAS scores, the trend of the slope of FIQ during follow-up was similar. The improvement in FIQ may be due to the combined effect of pain reduction or patient expectations after tDCS.We also observed a significant improvement after 1 week of tDCS treatment based on FIQ. According to systematic reviews9. According to Fregni et al., when the patient brain is stimulated in different locations such as the dorsolateral prefrontal cortex, it can have anti-depressive effects in FM patients6. Although we stimulated the M1 cortex of FM patients, we did observe an effect on depression. This may be because depression is a chronic response to pain and decreases in pain may improve depression. Cortical brain areas implicated in depression include the dorsal and medial prefrontal cortex, the dorsal and ventral anterior cingulate cortex, the orbital frontal cortex, and the insula25. In addition, pain-related brain regions include the prefrontal cortex, anterior cingulate cortex, insula, amygdala, hypothalamus, periaqueductal grey, rostral ventromedial medulla, and dorsolateral pons/tegmentum26. The brain regions involved in depression and pain are closely related. One longitudinal study reported a bidirectional relationship between depression and pain27. The intensity of the nociceptive pain stimulus has been associated with activation of central sensitization and psychological factors including depression28. Therefore, the antidepressant effect in this study may be due to the sequential effect of improving pain, and not the depressive symptom itself. In addition, M1 cortex stimulation may be one of the targets for the treatment of depression in patients with FM.We observed a significant improvement in depression after tDCS in FM patients. Of the three trials focusing on tDCS by Fregni et al., Valle et al., and Antal et al., there was no significant change in BDI after M1 stimulation30. Thus, the management of fatigue can be challenging for FM patients. Similarly, decreases in fatigue may be considered an additional effect of decreased pain. Therefore, tDCS may decrease fatigue in FM patients.Our study showed an improvement in fatigue after tDCS treatment. Fatigue in FM patients is a complex manifestation affected by various factors such as pain intensity, muscular tenderness, psychological distress, and low physical function9, the most common side-effect of tDCS is a tingling sensation, nausea, headache, and dizziness. A meta-analysis by Hou et al. showed that the most common adverse effects were skin discomfort at the stimulation site, headache, neck pain, and dizziness11. A study by Fagerlund et al. showed that 21% of patients had adverse events such as neck pain, scalp pain, itching, burning sensation, sleepiness, trouble concentrating, mood changes, and skin redness31. Fregni et al. reported an adverse event in 27% of the M1 stimulation group and 9% of the sham stimulation group, and 1 patient was withdrawn due to headache6. Similar to previous reports, we found adverse events in 17.4% of patients and all reported events were minor and well tolerated. Thus, these findings support that tDCS is a safe treatment modality for FM patients.Lastly, there was no serious adverse event during and after tDCS treatment in this study. Based on a previous systematic reviewOur study was performed prospectively and in conjunction with routine clinical practice. The majority of FM trials do not allow concomitant medications and most FM patients are unwilling to discontinue their medications to participate in the clinical trial. Therefore, we assessed tDCS stimulation as an add-on treatment for FM patients with severe pain. In addition, we evaluated various parameters to explore the efficacy of tDCS treatment on pain and associated symptoms. As a result, we found that tDCS may play an important role in improving chronic pain, depression, and fatigue in FM patients. In addition, by showing that tDCS is more effective in patients with severe pain, this study suggests that tDCS could be used in clinical practice as a treatment modality.There were some limitations in this study. First, the participants were aware of their treatments, and a high expectation of treatment benefit, including a placebo effect, could have influenced the assessment of our results due to a lack of blinding and control groups. Conducting a true double-blind trial remains challenging in the absence of a valid sham comparison group for a non-drug treatment like tDCS. Nonetheless, in an attempt to mitigate the influence of preexisting beliefs and expectations, we explicitly informed potential participants that the study was designed to test the effects of a brain stimulation technique. Although we hoped to decrease expectations and minimize bias by not mentioning tDCS specifically, we recognize the limited generalizability of this trial due to inadequate blinding and limitation of single group study. Second, our study was conducted in a single tertiary care center. Thus, we could not represent characteristics of all FM patients and these results may not be generalizable. Third, we could not determine the optimal number of stimulation sessions, treatment interval, and booster regimen. Longer trials are required to establish the treatment regimen.We showed that tDCS has beneficial effects on pain, quality of life, and fatigue in refractory FM patients. Particularly, tDCS is effective at relieving pain severity in patients with severe pain. Our findings support the use of tDCS as a promising treatment in FM patients. Larger, well-designed, unbiased investigations of tDCS treatment are required to explore the mechanism of action, as well as the long-term risks and benefits, and to confirm our results in FM patients.