Pediatric burns are a common and often devastating injury. Treatment, reconstruction, and rehabilitation are painful experiences. For some, the experience triggers post-traumatic stress disorder and/or a chronic pain syndrome. Given the role pain plays as a major secondary disease, it must be addressed to achieve optimal healing. Regional anesthesia has been used extensively to manage postoperative pain and reduce the need for opioids following other surgical procedures in children. However, regional anesthesia is not widely used in pediatric burn care. We present a descriptive, retrospective case series of 15 pediatric burn patients who received regional anesthesia as part of their intra-operative pain management. In our patient population, we saw low levels of anesthetic as well as opioid usage with well-controlled pain. In this cohort, 93% of patients scored a 0/10 on the Face, Legs, Activity, Cry and Consolability (FLACC) scale for pain by post-anesthesia care unit (PACU) discharge, with an average PACU stay of 70 minutes. Thirty-three percent of patients received no opioids, with the average opioid dose being 0.06mg/kg morphine equivalents. This case series serves to make clinicians aware of the feasibility of use and benefits of regional anesthesia in pediatric burn patients requiring operative repair. Burn injuries are the most common injury to pediatric patients in the world, accounting for approximately 2500 fatalities annually in the United States . Of thosPhysicians have historically used opioids to manage pain from burn injuries. Even when multi-modal analgesics such as acetaminophen, non-steroidal anti-inflammatory medications, and gabapentin are used, optimal pain control is often not achievable . One of The benefits of this decreased opioid use are multifold: improved bowel function, decreased potential for short- and long-term opioid sensitization, decreased need for weaning and dependence, and reduced potential for long-term psychological effects. In addition to analgesia, the sympathectomy-induced vasodilation of local anesthetics increases tissue blood flow and thus possibly improves local wound healing. Though little literature exists specific to burn healing, it has been shown that regional anesthesia decreases the failure rate of arteriovenous fistulas via a similar mechanism .The aim of this case series is to make clinicians aware of the feasibility of use and benefits of regional anesthesia in pediatric burn patients requiring operative repair. This article was previously presented as a meeting abstract at the 2020 Society of Pediatric Anesthesia annual meeting on February 29, 2020. This article was previously posted to the medRxiv preprint server on November 25, 2020.The study occurred at a university tertiary health care system that is an American Burn Association verified burn center. The patient database from the acute pediatric pain and regional service, which contains all regional blocks performed as well as any complications found, was manually examined by two people from February 2019 to October 2019. Anesthetic records of all patients under 18 years of age who received a regional anesthetic block for operative repair of burn injuries were identified. We then analyzed the perioperative period of these patients to determine the type of regional block, type and dose of local anesthetic used, intra-operative analgesic and anesthetic usage, anesthesia time, as well as immediate post-operative analgesic usage, pain levels, and time spent in the post-anesthesia care unit (PACU). We have no interests to declare. The IRB determined that this study did not require consent other than that for the anesthetics performed.We identified 15 patients aged seven months to 14 years who received general anesthesia and an appropriate regional block to cover both graft and donor sites for surgical burn debridement and grafting. Based on the American Society of Anesthesiologists (ASA) criteria, all patients were classified as ASA I or II. All regional blocks were performed after induction of anesthesia but prior to surgical incision. No complications with regional anesthesia were noted. All patients except one received up to 2.5 mg/kg of Bupivacaine 0.25% with or without clonidine depending on the block type; the other received 2.5 mg/kg of 0.5% Ropivacaine. All patients except one received approximately half the minimum alveolar concentration (MAC) of sevoflurane for the duration of their anesthetic. The only opioid given intra-operatively was fentanyl. Overall average intraoperative fentanyl dosing was 1.2 mcg/kg, with most patients receiving 0.5-0.9 mcg/kg. In addition, 9/15 patients received dexmedetomidine (average dose 0.6 mcg/kg) and 3/15 ketamine (average dose 0.75 mg/kg). Four patients received acetaminophen at either 10 mg/kg or 15 mg/kg based on their age. Two patients received 0.5 mg/kg of ketorolac. One-third of patients received no analgesic adjuvants in addition to the regional block and opioid. When examining pain scores and PACU stay, we found the following. Pain scores were recorded using the Face, Legs, Activity, Cry, Consolability (FLACC) scale, a behavioral pain assessment scale used for patients who are unable to self-report. Scores range from zero to ten, with zero being no pain. Sixty-seven percent of patients had FLACC scores of 0 upon arrival to the PACU. This rose to 93% by discharge, with an average discharge time of 70 minutes (range 33-158 minutes). Average opioid use in the PACU ranged from 0-0.2 mg/kg morphine equivalents with a mean of 0.06 mg/kg. One-third of patients received no opioids in the PACU, even after patients had recovered from anesthesia and met discharge criteria. Table Undertreated acute pain can lead to chronic pain and psychiatric maladies such as post-traumatic stress disorder . PediatrOne major benefit highlighted in studies on regional anesthetic block use is decreased PACU length of stay . ShorterInsufficient literature exists describing regional anesthesia use in pediatric burn patients. This case series serves as a model and demonstrates the feasibility of regional anesthetic block use in pediatric patients requiring operative repair of burn injuries. In our patient population, we achieved low FLACC scores with minimal opioid use and no complications from the regional blocks.This series is limited by its retrospective, descriptive nature. As such, patients received a variety of adjuvant pain medications depending upon the anesthesia care team and post-operative nurse. One patient received the highest post-operative opioid consumption despite FLACC scores of zero. This was likely attributed to individual nurse familiarity with regional blocks and could be alleviated with time and education. Future prospective studies comparing matched cohorts with and without blocks would further stratify the benefits of regional anesthesia in pediatric burn patients.Another important limitation of this study was the focus on the immediate perioperative period. Burn injury has multiple points of insult that include the initial burn as well as subsequent dressing changes. In addition to the initial injury, repetitive insults from treatments and dressing changes further traumatize children. Indeed, many children view dressing changes as the most traumatizing aspect of their burn injury . ChildrePain from burns can be excruciating and difficult to control. Excellent intraoperative and post-operative control can decrease experienced pain and suffering throughout the course of treatment. We presented a 15 patient case series of pediatric burn patients requiring operative grafting and debridement who received both general and regional anesthesia. Our patient population demonstrated excellent pain control with minimal opioid use. Clinicians should be aware of the feasibility and benefit of regional anesthesia in this patient population. Burn surgeons should discuss with anesthesiologists the possibility of regional anesthesia in their pediatric burn patients. The discussion of catheter placement for longer-term pain control should be visited as well.


Consultation referral from gastroenterologists to generalists could generate new possible diagnoses in approximately 70% of patients with undiagnosed chronic abdominal pain.This study aimed to investigate consultation outcomes from gastroenterologists to generalist physicians for the diagnostic workup of undiagnosed chronic abdominal pain. This was a single-center, retrospective, descriptive study. Patients were included who were ≥15 years old and consulted from the Department of Gastroenterology to the Department of Diagnostic Medicine, to establish a diagnosis for chronic abdominal pain, at the Dokkyo University Hospital from 1 April 2016 to 31 August 2020. We retrospectively reviewed the patients’ medical charts and extracted data. A total of 12 cases were included. Eight patients (66.7%) were diagnosed with and treated for functional gastrointestinal disorders (FGID) at the Department of Gastroenterology; their lack of improvement under treatment for FGID was the reason for their referral to the Department of Diagnostic Medicine for further examination. After this consultation, new possible diagnoses were generated for eight patients (66.7%). Six of the eight patients (75.0%) were diagnosed with abdominal wall pain (anterior cutaneous nerve entrapment syndrome,  Abdominal pain is one of the most frequent complaints for which patients seek medical attention. Although advances in diagnostic technology have made it possible to diagnose the causes of abdominal pain quickly and accurately, there are still patients who have undiagnosed chronic abdominal pain . To obtaAbdominal wall pain  is a key etiology in patients who have undiagnosed abdominal pain . AccordiThe characteristics of patients who are good candidates for consultation from gastroenterologists to generalists remain unknown. Therefore, we conducted this study to reveal the outcomes of consultation from gastroenterologist to generalist for diagnostic workup of undiagnosed abdominal pain, and also to reveal the demographics of abdominal pain, which gastroenterologists may wish to consult.This was a single-center, retrospective, descriptive study conducted at Dokkyo Medical University Hospital. Patients were included who were ≥15 years old and referred from the Department of Gastroenterology to the Department of Diagnostic and Generalist Medicine, for establishing a diagnosis of abdominal pain, from 1 April 2016 to 31 August 2020. Patients whose abdominal pain persisted less than two weeks or who had fever were excluded. The study was approved by the Independent Ethics Committee of the Dokkyo Medical University Hospital (No. R-41-10J). The requirement for obtaining informed consent was waived because this study was a retrospective data-only analysis.We retrospectively reviewed the subjects’ medical charts and extracted data regarding sex, age at the time of the referral visit, time from the onset of illness to referral, number of institutions or departments visited before referral, details of the histories of abdominal pain , details of the examinations, and the therapeutic interventions performed at the Departments of Gastroenterology and Diagnostic and Generalist Medicine, respectively, the final diagnosis, and the prognosis. Details of the examinations and therapeutic interventions included abdominal tenderness (including location), Carnett’s sign, laboratory tests, abdominal plain radiography, abdominal computed tomography (CT), magnetic resonance cholangiopancreatography (MRCP), abdominal ultrasonography, upper and lower gastrointestinal endoscopies, and the type of therapy . For confirmation of the diagnosis of abdominal wall pain, we used the criteria that abdominal wall pain diagnosis must include either a positive Carnett’s sign, localized extent of pain, or pain elicited only by certain movements, and that no other diagnostic test findings could explain the symptoms ,11,12.U test. Categorical data were compared using the chi-squared test or Fisher’s exact test. p-values < 0.05 were considered statistically significant. All statistical analyses were performed using R version 3.6.3 software .Continuous data are presented as median (25th and 75th percentiles) or range. Categorical data are presented as counts and proportions (%). Continuous data were compared using the Mann–Whitney n = 4), followed by epigastric (n = 3), left upper quadrant (n = 2), mid lower (n = 2), right upper quadrant (n = 1), and right flank (n = 1)  . Only onThe numbers indicated the case number in n = 0, 0.0%). Blood tests , abdominal CT , and upper gastrointestinal endoscopy  were conducted in most of the patients. However, lower gastrointestinal endoscopy , abdominal ultrasonography , and MRCP  were conducted selectively. Eight patients (66.7%) were diagnosed and treated as FGID . In all eight patients, lack of improvement under treatment for FGID was the reason for their referral to the Department of General Medicine.Carnett’s sign was not documented in all cases . In total, new possible diagnoses were generated in eight patients (66.7%). In these patients, six (75.0%) were diagnosed as abdominal wall pain . Of the other patients, one was diagnosed as chronic pelvic pain, and the other as iron deficiency. In patients with abdominal wall pain, only one (16.7%) was aware of localized pain; the other five (83.3%) complained of relatively widespread pain. None of the patients with abdominal wall pain had weight loss; all of them had localized (not multiple or diffuse) tenderness in the abdomen.Carnett’s sign was documented in six cases (50%). Additional diagnostic tests were performed in only four cases , n = 2; eperisone, n = 1; pregabalin, n = 1; tender point injection, n = 2; neurectomy, n = 1; iron supplementation, n = 1, and magnesium oxide, n = 1. In the nine cases (75%) that were followed-up , symptoms improved in 2 (1 ACNES and 1 iron deficiency).The treatments provided were as follows: exercise, There were no statistically significant differences between patients with and without abdominal wall pain .In this study, we found that new possible diagnoses were generated in 66.7% of 12 patients who were referred from gastroenterologists to generalists for undiagnosed chronic abdominal pain in the setting of a tertiary hospital. Before referral to the generalists, 66.7% of patients were diagnosed as FGID. In the patients who obtained new possible diagnoses after referral to the generalists, abdominal wall pain accounted for 75%; ACNES was the most common diagnosis.The prevalence of abdominal wall pain in the study (50%) was higher than that has been reported in previous studies 15–28%) ,14,15. T–28% ,14,Chronic abdominal pain is often treated as functional pain because of the absence of organic abnormalities in various tests . In thisAbdominal wall pain may present with atypical patterns. Among the patients in our study, the typical presentation included the duration of symptoms and the region of pain. Abdominal wall pain lasting longer than one year is reported to be common . In thisCarnett’s sign is an important physical examination for the diagnosis of abdominal wall pain . CarnettHowever, for patients with chronic abdominal pain, it may not be tested as much as might be expected in clinical practice. Carnett’s sign was not documented in all patients by the gastroenterologists; it was documented by the generalists in only 50% of the patients. This might be explained by the fact that abdominal wall pain remains unfamiliar to physicians, as it is rarely described in detail in textbooks ,5. Also,Early diagnosis of abdominal wall pain by eliciting Carnett’s sign can prevent unnecessary diagnostic journeys such as overtesting, frequent clinical visits, and referral, and also can prevent adverse events from ineffective treatment ,23. HoweTrigger point injection is another valuable diagnostic investigation for the diagnosis of chronic abdominal pain. In general, the trigger point injection test is positive when abdominal pain improves by anesthetic injection to the point of tenderness, and the positive result of trigger point injection indicates the diagnosis of abdominal wall pain ,12,24. WThis study has several limitations. First, since this was a small retrospective study conducted at a single center, the results should be used only for research and hypothesis generation; they should not be considered as generalizable evidence. In particular, the result of the analyses did not provide any significant difference, which seemed mainly due to the small sample size. Second, since definitive confirmation of the abdominal wall pain diagnosis is difficult, and Carnett’s sign was not documented in 50% of the patients in this study, the diagnosis could be wrong in some patients. Third, since not all patients with undiagnosed chronic abdominal pain were referred from gastroenterologists to generalists, selection bias could not be avoided.n = 12) were included for around 4.5 years in this study. First, some physicians did not have the idea that consultation to the Department of Diagnostic and Generalist Medicine may be an option for detecting the cause of chronic abdominal pain. Indeed, to the best of our knowledge, no previous study reported the results of diagnostic consultation from the gastroenterology department to the general medicine department for patients with chronic abdominal pain. The absence of such a study would indirectly support the possibility that diagnostic consultation from gastroenterology departments to general medicine departments is not routinely performed. Second, only the most diagnostically difficult cases that require well-honed medical history and examination skills by general physicians after a detailed investigation in the Department of Gastroenterology might have been referred for consultation to the Department of Diagnostic and Generalist Medicine. Typical cases of abdominal wall pain seemed not to be consulted because gastroenterologists could diagnose them. This may have resulted in a decrease in the number of participating cases. Third, some patients were referred directly from a clinic or a hospital to the Department of Diagnostic and Generalist Medicine, not via the Department of Gastroenterology, when the physician in the clinic or hospital thought that other than gastroenterology disease was a cause of abdominal pain. These cases were not included in the inclusion criteria of this study, but they could have been originally referred to the general medicine department after seeing the gastroenterology department once.There seemed several reasons that relatively small participants (Consultation from gastroenterologists to generalists in the tertiary hospital could generate new possible diagnoses in around 70% of patients with undiagnosed chronic abdominal pain. Patients with chronic abdominal pain diagnosed as FGID could be indicated for referral from gastroenterologists to generalists in order to seek alternative diagnoses. Abdominal wall pain should be considered as a diagnosis even in elderly patients who have relatively widespread pain; physicians should perform Carnett’s sign in these cases.


GLA gene, encoding the lysosomal hydrolase α-galactosidase A. The consequent reduced enzyme activity results in the toxic accumulation of glycosphingolipids, particularly globortriaosylceramide (Gb3 or GL3), in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin. Neuropathic pain is the most common manifestation of Fabry disease and can be extremely debilitating. This often develops during childhood and presents with episodes of burning and sharp pain in the hands and feet, especially during exercise and it is worse with increased heat or fever. It is thought to be due to ischaemic injury and metabolic failure, leading to the disruption of neuronal membranes and small fibre neuropathy, caused by a reduced density of myelinated Aδ and unmyelinated C-fibres and alterations in the function of ion channels, mediated by Gb3 and lyso Gb3. It is important to confirm small fibre neuropathy before any Fabry disease treatment modality is considered. There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role of available therapies. The current Fabry disease guidelines are in favour of pharmacological management as the first-line treatment for pain associated with Fabry disease. Refractory cases would benefit from a rehabilitation approach with interdisciplinary input, including medical, physiotherapy and psychological disciplines and including a Pain Management Programme.Fabry disease is a progressive X-linked lysosomal storage disease caused by a mutation in the  GLA gene, encoding the lysosomal hydrolase α-galactosidase A  [3), and lyso-Gb3, the decylated form of Gb3 in blood vessels, renal epithelia, myocardium, peripheral nervous system, cornea and skin [Fabry (sometimes referred to as Anderson–Fabry) disease is a progressive X-linked lysosomal storage disorder caused by a mutation in the α-Gal A) . This reand skin .The estimated prevalence of Fabry disease is 1:40,000–170,000 . The sysIn untreated males, the median life expectancy is approximately 50 years ,7. MortaPain is a hallmark of classical Fabry disease and is a significant feature particularly within the first two decades of life. This has implications for normal childhood development, academic progress and family life. Pain has a significant impact on both male and female patients and leads to a significant reduction in quality of life compared to the general population. This appears to coincide with depression, anxiety and chronic fatigue in a significant percentage of people living with Fabry disease . NeuropaThis review presents the pathophysiology and investigations of pain in adults with Fabry disease, with a focus on the multidisciplinary team (MDT) management of different types of pain.Acroparesthesiae (neuropathic pain) is the most common manifestation of Fabry disease, occurring in up to 62–80% of classical hemizygous male patients and 30–65.3% of heterozygous female patients ,11,12. LGLA gene makes it difficult to predict which patients will experience pain [Although Fabry disease is an X-linked disorder, it is becoming clearer that heterozygote females develop acroparaesthesiae at rates in excess to that seen in the general population ,16. Howence pain .Pain in Fabry disease is dependent on the amount of residual enzymatic activity. Hence, pain is a hallmark of disease in the classical phenotype with no residual enzymatic activity. However, there may be a wide spectrum of phenotypes ranging from classical to later onset type in males , and a wPain often develops during childhood and presents with episodes of burning, sharp, stabbing and shooting pains in the hands and feet, especially during exercise and it is worse with increased heat or fever . PatientIn females with classic Fabry disease, small nerve fibre dysfunction remains largely restricted to the calf. However, males with classical Fabry disease, show additional involvement of the thigh with disease progression ,17. SmalEvoked pain, triggered by stimuli including brushing, pressure or cold, has been reported in 31–45% of patients . While eSignificant heterogeneity in thermal and mechanical responses among Fabry disease patients depends on severity and progression of the disease.Additional information is required to determine whether small fibre neuropathy is Fabry disease related or caused by other conditions giving rise to damage to small nerve fibres. Other symptoms and signs of Fabry disease crises include hypohydrosis, reduced cerebrovascular reactivity and labile blood pressure. Post-prandial abdominal pain with alterations in gastrointestinal motility and early satiety have been also described . Many FaChronic pain, lasting over 3 months, is reported by 12–40% of patients and affects joints in the legs, shoulders, back, but also abdomen and head ,26. It i3) on dorsal root ganglia and the peripheral nervous system which lead to cell swelling [The processes involved in the development of pain in Fabry disease are complex and are thought to be mainly neuropathic in nature, due to the involvement of Lyso-globotriaosylceramide , acid sensing (ASIC), and hyperpolarisation-activated cyclic nucleotide-gated (HCN) ion channels. In Fabry disease, the slowing of action potential generation from nerve fibres, which is commonly related to sodium channel dysfunction, was not affected, indicating that sodium channel function and expression is normal in C fibres from Fabry disease patients ,40. In aFurther changes in voltage-dependent sodium channel  ,39, voltNTR) plays a critical role in nerve growth factor (NGF)-induced sensitisation of capsaicin-sensitive small-diameter sensory neurons [The characteristic pathophysiological vasculopathy seen in Fabry patients causing an alteration of nitric oxide liberation, leading to an abnormal vascular response and reduced perfusion, could be linked to pain conditions associated with physical stress in Fabry. Politei et al. (2016) suggested that the application of capsaicin cream or lidocaine may reduce physical stress induced pain in Fabry patients . In part neurons ,47 and t neurons .NTR, led to the improvement in Gb3-induced allodynia [NTR signalling [Inflammation has been postulated as a potential pathomechanisms of Fabry disease  with NGFllodynia . It has gnalling .In addition, in vivo studies have shown involvement of pro-inflammatory cytokine mediators in the immune system, including TNF-alpha, IL-1beta, TLR4, and IL-6, suggesting that pain, apart from being neuropathic, may also encompass inflammatory components ,54.Lysosomes degrade and recycle organelles in a process known as autophagy. The degradation of mitochondria is known as mitophagy. Mitophagy prevents the build-up of reactive oxygen species (ROS) in cells including neurons . The effThe effect of GB3 on inflammation and ROS is complex. The intracellular accumulation of GB3 leads to a reauction in eNOS and a concomitant increase in the iNOS, leading to NO production and increased ROS. Furthermore, ROS reduced glutathione (GSH) levels. GSH is the key non-enzymatic antioxidant, which preferentially oxidises key reactive species thus preserving more important biomolecules ,58.ROS lead to an alteration in superoxide dismustase:catalase activity ratio (SOD), which is a key antioxidant within mitochondria . Its dowThere is some evidence that cholinergic nerve fibre dysfunction contributes to the altered nitric oxide metabolism in Fabry disease . MoreoveCentral sensitisation and altered pain modulation are also likely involved in patients with Fabry disease . Intermi2+) influx which is lyso-Gb3 dependent [Pain in Fabry disease also consists of nociceptive or inflammatory components, as demonstrated by its responsiveness to non-steroidal anti-inflammatory drugs (NSAIDs), in many Fabry disease patients ,16,17. Iependent .In heterozygote females, in the absence of other manifestations of Fabry disease, confirmation of small fibre neuropathy using insensitive traditional techniques  is usually required before commencement of enzyme replacement therapy (ERT) or any other treatment modality is considered .The severity of neuropathy closely correlates with plasma levels of Gb3 or its metabolites ,44. UnfoThe advantage of skin biopsy is its effectiveness in assessing small fibre neuropathy when compared to electromyography and nerve conduction studies. It can be also repeated multiple times to monitor disease progression or treatment efficacy .In such cases, however, it is also likely that improvements in response to ERT or chaperone therapy will be difficult to detect given the level of structural nerve fibre damage that has already occurred.There is a clinical need for novel techniques for assessing small fibre function to improve detection of small fibre neuropathy and expand the role for the available therapies  Table 2Table 2.Microneurography is a minimally invasive technique which involves using a microelectrode  to record nerve activity in a superficial nerve ,64. The The recent development of enzyme replacement therapy (ERT) for Fabry disease has revolutionised outcomes and has become the standard of care in affected patients . Other oERT has been shown to not only prevent major organ complications, but also to reduce neuropathic pain. Although ERT did not impact intra-epidermal nerve fibre density , small nWhilst pain-related quality of life has been shown to improve in response to ERT, a significant proportion of patients respond incompletely, presumably because of the presence of irreversible nerve damage . In chilSeveral studies investigated treatment response to ERT. In one placebo-controlled trial, Gb3 clearance in skin from the back was observed 20 weeks after the initiation of ERT . AnotherMigalastat is an oral pharmacological chaperon therapy (daily tablet), which stabilises amenable mutant forms of α-Gal A in the endoplasmic reticulum, thus facilitating passage to the lysosomes and enzymatic breakdown of Gb-3. The pain severity component of the Brief Pain Inventory (BPI) showed that patients had mild pain at baseline and it remained stable over the 18 month treatment period, when patients were treated with Migalastat . Whilst Lucerastat, an iminosugar, is currently under investigation in a phase 3 study of Fabry disease with neuropathic pain as the primary end point .Gene therapy is the delivery of a therapeutic gene for cellular expression to alter a disease phenotype. Recombinant lentivirus base gene therapy and adeno-associated virus therapy have begun in Fabry disease . Gene edPain therapy in Fabry disease remains an unmet need. When considering therapeutic goals with respect to pain in Fabry, patients can be divided into two groups, namely, patients with pain and significant associated distress, and those with predominantly neuropathic pain without overt distress. The priority in the first group is to optimise their analgesics and implement holistic support, whilst in the second group a largely medical approach is employed. Patients should be encouraged to adopt pain diaries and the BPI and SF36 (Short form 36) or EQ5D uses as quality of life scores on a 6 monthly basis ,77.Despite clarity with respect to therapeutic goals, there appears to be a limited consensus on how best to effectively manage pain in this cohort of Fabry disease patients. Further to recent European recommendations on the pain management in Fabry disease , a systeGastrointestinal symptoms and abdominal discomfort can be managed with dietetic recommendations regarding meal content, portion sizes and frequency. Nausea and vomiting can be treated with metoclopramide and domperidone, with motilin receptor agonists added in case of severe symptoms . FrequenA multidisciplinary approach is important when forming an analgesic care plan involving not just metabolic and pain specialists, but also specialist pharmacists, pain psychologists and physiotherapists in the service. The management of pain in Fabry disease is challenging as a result of the unique interplay between a number of factors. Neuropathic pain, which is normally challenging to treat, is combined with a presentation in patients with multiorgan dysfunction, often limiting pharmacological management. In addition, the most severe symptoms are often found in males starting in their youth at a time of great flux in their psychosocial development. Fabry disease may be well recognised within the family unit but poorly recognised and understood by the medical community as a whole.High rates of depression have been reported in patients with Fabry disease. Pain is a significant contributory factor to depression  and anxiGiven the range of developmental, physical, and neurological challenges associated with Fabry disease, its association with depression is unsurprising. However, faced with this context, both patients and clinicians are at risk of viewing such negative psychological associations as an inevitable consequence of Fabry disease. Indeed, this perception is consistent with the finding that the magnitude of decrement in social adaptive functioning correlates with anxiety and depression . HoweverIn Fabry disease, examples of such modifiable factors include behavioural and psychological moderators (such as overexertion and stress) of physical symptoms such as pain. The cognitive model underpinning cognitive behavioural therapy  emphasisPsychological treatment in the form of cognitive behavioural therapy has been used in the treatment of anxiety and depression for several decades ,92, and Depressive symptoms have a significant impact on neuropsychological functioning in up to 16% of patients . TherefoThe best evidenced rehabilitation treatment for patients with persistent pain and disability is the group Pain Management Programme. These programmes are an interdisciplinary treatment approach including medical, physiotherapy and psychological input and are based on Cognitive Behavioural Therapy, typically providing around 36 h of rehabilitation treatment .Whilst the majority of patients attending Pain Management Programmes have musculoskeletal pain, the British Pain Society (2013) notes that “a minority have visceral, neuropathic, phantom or central pain, and/or pain from identified disease such as osteoarthritis and rheumatoid arthritis”. Therefore, Pain Management Programmes are effectively used in our tertiary Adult Metabolic Centre for patients with Fabry disease.Our model of working with Fabry disease  has evolved to encompass joint metabolic and pain clinics, involving both patients and their carers. We see on average 4–5 Fabry patients per joint clinic, the majority of whom are male and with moderate to high psychometric scores. This allows a combination of expertise in metabolic and pain medicine and the involvement of a selected number of the rehabilitative interdisciplinary team, featuring psychologists, pain physiotherapists and occupational therapists.At our institution, pain in Fabry disease patients is managed in a holistic manner. Adult and transitional patients with pain first have access to the pain clinic in a joint clinic often with parents and carers. As part of this assessment, routine care with involvement of other specialties is initiated and a range of psychometric scores are completed by the patient, to act as a baseline and help inform the next steps in holistic control and management of pain and quality of life. These psychometric scores include, the PHQ-9 score, GAD-7 score, TSK and PCS scores, to assess for depression, anxiety, kinsesiophobia and catastrophisation, respectively. Specific Fabry questionnaires such as the Fabry scan questionnaire may also be employed . This isPhysiotherapy and psychology colleagues work collaboratively to address issues such as pacing, exercise and activity medication, passive cooling strategies, sleep hygiene, goal setting, flare up management, confidence, and identity. Pharmaceutical agents are used alongside this where appropriate.The interdisciplinary team must be mindful of the impact of Fabry disease on educational attainment, marital status, social support and employment which are significantly affected by the effects of the disease .As an example, a 45-year-old female patient with Fabry disease benefited from this treatment at our institution. The preliminary assessment identified that stressors often aggravated her pain symptoms, and this in turn led to avoidance of potentially stressful situations, which then contributed to increased disability. Activity cycling was also a feature. This pattern involves determined efforts to undertake activities, which fuels overexertion and is then followed by an increase in pain and reduction in activities. Treatment goals developed with the Pain Management Programme Team included (i) increasing understanding and effective management of anxiety to reduce the impact of stress on pain, (ii) improved stress management skills to enable a reduction in avoidant coping and thereby to reduce disability, (iii) problem-solving skills to manage work demands and avoid activity cycling, and (iv) improved activity pacing skills to enable a return to leisure activities. Standard physical outcome measures showed significant gains in physical function after the Pain Management Programme. Psychometric outcome measures at 12 months post-programme showed substantial improvements in depression, anxiety, and pain catastrophising.In addition it is recommended that activities that may trigger painful crises such as emotional stress, physical exertion and temperature changes are minimised .Patients are advised to monitor when painful crises occur and to try to avoid anything which may precipitate a crisis. Passive cooling strategies can be utilised to improve tolerance to exercise and heat induced pain. Gastrointestinal pain can be managed with smaller meals, low-fat diets and motility agents whilst the use of antianginal agents may also be helpful for ischaemia angina pectoris-related pain.The management of pain in Fabry disease is challenging as a result of the unique interplay between a number of factors. Pain in Fabry disease may affect patients from childhood. Novel techniques in detecting small fibre neuropathy are needed, whilst traditional disease modifying treatments have a limited impact on pain.Neuropathic pain, which is not normally easy to treat, is further complicated by patients with multiorgan dysfunction, often limiting pharmacological management. In addition, the most severe symptoms are often found in males starting in their youth, at a time of great flux in their psychosocial development.Ultimately, patients may derive great benefit from interdisciplinary rehabilitation. A multimodal pharmacological approach using a combination of neuropathic agents such as the gabapentinoids and duloxetine may facilitate a reduction in neuropathic pain whilst achieving an opioid-sparing effect. In turn, a reduction in neuropathic pain may also facilitate greater engagement with interdisciplinary rehabilitation to achieve a better quality of life.


BackgroundThis study investigates whether the use of medical cannabis (MC) in patients with chronic back pain is associated with a decreased opioid prescription.MethodsThe study included 186 patients with chronic back pain who were certified for MC use. The average morphine milligram equivalent (MME)/day of opioid prescriptions filled within the six months prior to MC certification was compared to that of six months after. Pain and disability questionnaires were distributed at three, six, and nine months post-certification.ResultsPatients who started at less than 15 MME/day and patients who started at greater than 15 MME/day decreased from 15.1 to 11.0 , 3.5 to 2.1 , and 44.9 to 33.9 , respectively. Pain and disability scores were improved at follow-up as well.ConclusionMC use reduces opioid prescription for patients with chronic back pain and improves pain and disability scores. Opioid abuse is an ongoing problem, with opioid-related deaths nearly quadrupling between 1999 and 2015 in the United States ,4. The bMedical cannabis (MC) is an emerging therapeutic option for adult patients with chronic pain, but its efficacy is not fully confirmed. MC has been approved for the treatment of pain in over 30 states as of 2020, making it much more widely available . MC has There are limited data to support MC as an effective replacement for opioids. However, population studies show that the legalization of MC has been associated with reduced mortality due to opioid overdose, reduced opioid-related hospitalizations, and decreased opioid prescription . This stPatient outcome measures for this study were obtained by querying a prospectively collected cannabis data repository. Patients with a diagnosis of chronic musculoskeletal noncancer low back pain who were certified for MC between February 2018 and July 2019 were prospectively enrolled and included. Patients were included in the analysis if they had a diagnosis of the spine, were not indicated for surgical or injection treatment, and were actively consuming opioids. Exclusion criteria included patients with all non-spine diagnoses, having undergone surgery within six months before or after MC certification, and not consuming opioids at the time of MC certification.Patient demographic information, visual analog scale (VAS) back pain score, numeric back pain intensity, numeric back pain frequency, VAS right leg pain score, VAS left leg pain score, numeric leg pain frequency, numeric leg pain intensity, and Oswestry Disability Index (ODI) scores were collected. VAS and numeric scales for pain, as well as the ODI, are commonly used metrics for the evaluation of lower back pain -16. ScorAll physicians involved with MC certification previously attended a four-hour continuing medical education (CME) course and applied to the Pennsylvania Department of Health to become approved practitioners. MC was certified for patients who met the criteria by being a resident of Pennsylvania and suffering from one of the 23 state-approved medical conditions . During Data regarding filled prescriptions of all controlled substances were gathered using Pennsylvania’s Prescription Drug Monitoring Program (PDMP) system. PDMP is a state-run program that collects information on all filled prescriptions for controlled substances and can be accessed online by licensed providers. Data on opioid prescriptions that were filled within six months before and after MC certification were collected into a password-protected Microsoft Excel  database. Opioid use was calculated based on the average morphine milligram equivalents (MME) filled per day over the six months before and after MC certification. Patients were then stratified into greater than or less than 15 MME/day groups based on average MME per day prior to MC certification. A threshold of 20 MME/day has been used in the past based on data showing increased rates of overdose in patients taking over 20 MME/day . The thrStatistics were calculated within Microsoft Excel using a paired, two-tailed t-test for paired data, a two-tailed t-test with unequal variance for non-paired data, and a single-factor analysis of variance for multi-group comparison. An alpha threshold of alpha = 0.05 was applied for all unique significance tests.A total of 632 patients were certified for MC for a musculoskeletal pain diagnosis between February 2018 and July 2019. Of those patients, 477 had a diagnosis related to chronic low back pain  between six months pre-MC to six months post-MC Figure . The perPain scores and ODI scores were measured at baseline (n = 100) and three (n = 60), six (n = 44), and nine months (n = 33) post-MC certification. Compared to baseline, VAS back pain score decreased significantly from 73.1 to 58.1 (p < 0.01), 53.2 (p < 0.01), and 51.9 (p < 0.01) at three-, six-, and nine-month time points, respectively Figure . The samData on the route of MC administration were collected for 144 (77.0%) patients. A total of 68 patients 47.2%) used only a single route, 54 patients 37.5%) used two routes, 20 patients (13.9%) used three routes, and two patients (1.4%) used four routes. Vaporized oil and sublingual tincture were used most commonly, with 60 patients (41.7%) using each (Table % used on7.5% usedData on adverse effects were collected for 71 (38.2%) patients. Of respondents, 40 patients (56.3%) did not feel intoxicated or high, and 31 patients (43.7%) felt intoxicated or high  . Based oCurrent literature is mixed over whether the introduction of MC is associated with decreased opioid use in patients with chronic pain. While some studies have shown decreased opioid usage with MC, other studies have reported no change or increased prescription drug use ,20-26. TThe mechanism of action of MC involves two major components: THC and CBD. THC activates cannabinoid receptors type 1 and 2 (CB1 and CB2) . THC actPrevious literature regarding the route of administration has shown that various routes differ in side effect profiles . There iWhile most cohort studies utilize a follow-up period within six months following MC initiation, a study conducted in California tracked long-term opioid usage of opioids for chronic back pain and showed that stopping opioid usage after MC initiation takes an average of six years ,22,27. OCurrently, MC is recommended in a limited role to select patients with a terminal illness or chronic refractory pain due to an overall lack of substantial clinical evidence . Our finGaps in current literature include but are not limited to proper MC dosing, long-term efficacy, and side effect profiles. This study begins to look at which opioid usage profiles are best served with MC recommendations, but further study is needed to identify formal indications. Federal rescheduling of cannabis to a Schedule III drug like dronabinol, the FDA-approved synthetic form of THC, would significantly improve the ability to conduct these highly warranted studies.This study has several limitations. First, it was an uncontrolled and observational study. Because MC remains a Schedule 1 drug, controlled trials are not currently possible without an “Investigational New Drug” trial approval from the US FDA. Tracking filled opioid prescriptions does not necessarily indicate the actual use of opioids. We could not account for any diversion of opioid usage. In addition, we could not track the acquisition of illicit opioids. Our study does not track long-term MC usage and may miss attrition. Due to the study design as well as a lack of data on MC safety profile, our study cannot directly comment on MC efficacy or current guidelines. This study did not allow for the correlation of pain and opioid reduction outcomes with specific cannabis products, phenotypes, cannabinoid ratios, or daily doses. Participants self-selected products at retail dispensaries and used a wide variety of cannabis and cannabis-infused products ad-libitum. Data on MC adverse effects have limited generalizability given the variability in patient MC administration.Among patients with chronic musculoskeletal noncancer back pain who were certified for MC, they filled a significantly reduced amount of opioid prescriptions post-MC compared to pre-MC. Upon MC certification, patients with lower levels of baseline opioid use have a high chance of stopping opioid use altogether. Patients show improved pain scores and daily function scores following MC certification. The use of multiple routes of administration simultaneously may be more efficacious in reducing opioid utilization.


In a previous study, we assessed a novel, remotely monitored carbohydrate restricted diet regimen including nutritional ketosis in patients with type 2 diabetes and reported significant improvements in weight, glycemic control, abdominal fat and inflammation from baseline to 2 years. Knee outcome measures were collected as a secondary outcome in the trial. This study aims to assess the effect of this intervention on knee functional scores and to identify if changes in weight, central abdominal fat (CAF), glycemic status and high sensitivity C-reactive protein (hsCRP) were associated with its improvement.n = 173) and usual care  trial participants with type 2 diabetes that reported knee pain at baseline. Knee outcome measures included the Knee injury and Osteoarthritis Outcome Score (KOOS) pain, symptoms, activities of daily living (ADL), sports and recreation function, and knee-related quality of life subscales, and total KOOS score were assessed from baseline to 2 years. Missing data at each time point were replaced with multiple imputation under the assumption of missing at random. To assess if the primary analysis of the knee scores changed under plausible missing not at random assumptions, sensitivity analysis was also performed using pattern mixture models. In CCI, we also assessed factors associated with the improvement of knee scores.This prospective analysis included continuous care intervention .Clinical trial registration: The online version contains supplementary material available at 10.1186/s12891-022-05258-0. Osteoarthritis (OA) is a painful and debilitating disease process affecting roughly 54.4 million adults 22.7%) in the United States annually . Knee OA2.7% in tAmong nonsurgical treatment options for knee OA, weight loss is routinely recommended and has been shown to significantly improve knee pain and function –15. In fWhile the relationship between bodyweight and knee osteoarthritis has been well established, more recent studies have explored diet as an independent modulator of knee OA. Preliminary studies suggest that diet may be an independent variable influencing knee pain in osteoarthritic mice . FurtherWhile ketogenic diets have been shown to be successful in treating diabetes and improving some forms of pain , 24–26, We postulate that a carbohydrate restriction intervention would improve knee pain and function scores and it is possibly driven by the improvement in weight, glycemic control, and inflammation. Therefore, in this study, we aim to evaluate the effect of this carbohydrate restriction intervention on subjective knee pain and function scores that were secondarily collected as part of the trial. In addition, we also assessed and identified factors that were associated with the knee improvements in the intervention. For the association analysis, we included outcome measures that were previously reported and commonly associated with knee pain and OA –19.2 and all participants provided written informed consent. The trial was an open-label, non-randomized, controlled, longitudinal study with patients divided into two groups: remotely monitored continuous care intervention (CCI) and usual care (UC). In the CCI regimen, participants self-selected to receive educational content either through on-site group meetings (CCI-onsite) or virtual delivery . The medical treatment and educational content were the same between the CCI-onsite and CCI-virtual, except the CCI-onsite group had additional clinic group meetings that ranged from weekly for 12 weeks to quarterly in the second year (26–28). All participants in the CCI arm were given access to a mobile health application (app) that allowed them to communicate with a team of healthcare professionals consisting of a personal health coach and health care provider (physician or nurse practitioner). These patients were educated and guided remotely to achieve nutritional ketosis, which typically included a daily dietary carbohydrate restriction to less than 30 g. Patients were also encouraged to measure body weight daily and input fingerstick blood glucose and beta hydroxybutyrate concentrations in the app allowing for continuous monitoring of patients’ diet adherence, progress and to guide their healthcare team to make appropriate adjustments. Since there were no significant differences in the knee outcomes including total KOOS and its individual subscale scores between the two education groups, the CCI-onsite and CCI-virtual groups were combined for the analyses in this study.The full detail of the study design, inclusion and exclusion criteria and the results from primary outcomes have been previously published , 33. ThiThe usual care group was recruited separately. This group consisted of T2D patients who began participating in a local diabetes education program with treatment by their primary care physician or endocrinologist and diet counseling by registered dietitians. No modification was made to their care for the study. This group served as a reference of diabetes disease progression under routine care within the same geographical area and health system.The recruitment of patients into the study were mainly based on the inclusion and exclusion criteria listed for the primary outcomes. There were 262 CCI and 87 UC participants with T2D enrolled at baseline for the main study. The study was not designed for assessing knee outcome; the knee subjective data were collected as a secondary outcome in the trial along with other questionnaires assessing sleep and depression symptoms. The KOOS questionnaires were administered to participants who completed their laboratory assessments by the study coordinator during their baseline, 1- and 2-years follow-up visit in the clinic. The patients completed paper-based questionnaires after their clinic visit. At baseline, there were some patients who failed to complete the questionnaire or sections of the questionnaire. At 1 and 2 years, in addition to patients not completing the questionnaire, missingness in the knee questionnaire data was also related to patients withdrawing from the study, and patients failed to attend their clinic follow-up visit after completion of their laboratory assessment.For the knee assessment, participants who reported no knee pain at baseline (based on their response to question P1 “How often do you experience knee pain” of the KOOS questionnaire) were excluded from analysis and those who reported knee pain at baseline or missing any baseline data were retained for further analysis  survey. The KOOS is a multi-dimensional questionnaire measuring five knee-related domains including pain, symptoms, activities of daily living, sports and recreation function, and knee-related quality of life. The KOOS and its individual sub-scores were used as a subjective measure to gauge patient knee pain and function with or without a diagnosis of knee osteoarthritis. Each section in the KOOS survey is scored on a normalized 0–100 scale (with 100 categorized as the best with no knee problems and 0 as the worse knee outcome). The total KOOS score was calculated as the averaged individual KOOS subscale scores (0–100). The Cronbach’s α coefficients between the KOOS individual sub-scores and total KOOS scores were excellent in all three time points (> 0.95).All data analyses were conducted using IBM SPSS Statistics for Windows, version 26.0 . We assessed the normality and linearity of the knee KOOS data including KOOS Symptoms, KOOS Pain, KOOS Activities of Daily Living (KOOS ADL), KOOS Sports and Recreation (KOOS Sport), KOOS Quality of Life (KOOS QoL) subscores and total KOOS score from all three time points using skewness and kurtosis .Descriptive statistics of the baseline characteristics were performed, and independent sample student t-tests were used to analyze differences in baseline characteristics between CCI and UC, and completers and non-completers (including dropouts). The difference in the proportion of missing data at each time point between CCI versus UC was assessed using Chi-Square test.Due to high degree of missingness in the knee outcome data. The primary assessment of KOOS total and subscores was performed under missing at random (MAR) assumption using multiply imputed dataset. A standard multiple imputation (MI) was performed to generate 50 imputed datasets. For within-group longitudinal changes from baseline to 2 years and between-group differences (CCI vs UC) at 1 and 2 years in the KOOS total and sub-scores, we conducted linear mixed-effects model (LMMs) with time as a repeated measure. The models included time, group effect (CCI vs UC) and time by group interaction as fixed effects and several baseline and demographic covariates (as listed in the Table To further investigate the possibility of the data missing not at random (MNAR), several sensitivity analyses were conducted using pattern-mixture models (PMMs) applying different scenarios of plausible departures from missing at random (MAR) assumption. The imputed values in the 50 MI datasets were multiplied by a sensitivity parameter delta (δ) representing the average difference between the observed values collected from the completers and those missing any values. For the total KOOS and subscores data, we reported a significant increase of at least 10% from baseline in CCI in the primary analysis using MI data with MAR assumption. Based on the primary analysis, we estimated a difference of 5 to 10% is considered as a reliable δ to assess the different MNAR scenarios. A comprehensive step-by-step detailed description of the sensitivity analysis using PMMs is included in the As an additional exploratory analysis only in the CCI group, we then assessed predictors associated with KOOS improvement. This analysis was performed among those who completed the study with available knee data at 2 years. We first performed unadjusted Pearsons’ correlations between changes in total KOOS and its subscale scores with changes in glycemic, weight, abdominal fat and inflammation at 1 and 2 years. Variables with significant correlations were then included in multivariate linear mixed-effects regression models with random intercepts and random time slopes. Six different models were generated to test the association between the total KOOS score and its individual subscale scores with these potential predictors. In these models, the time trend was controlled, and the predictors were modeled as a time-varying covariate. The models also included predictors by time interaction term to assess concurrent association over time between the predictor variables and KOOS. The models also included several baseline and demographic covariates  at 2 years among those who completed the study with available knee data at baseline and 2 years. We utilized a cut-off of 10  for MIC; those achieving a p-value =0.05/6 variables = 0.008 was used to determine statistical significance. For all other exploratory analyses, a p-value = 0.05 was used to determine statistical significance.For the primary aim of the paper assessing longitudinal changes in the total and individual subscale scores, a Bonferroni adjusted Patient baseline characteristics for knee scores and other demographic, metabolic and inflammatory variables among CCI and UC participants reporting knee pain at baseline are provided in supplementary Table p = 0.003).Missing data were encountered in all assessment time points even at baseline in both the intervention arms , CCI demonstrated a statistically significant improvement in total KOOS and all KOOS individual subscale scores at 1 year compared to UC patients [Table Among participants with knee pain at baseline  and 2 years (p < 0.01) in total KOOS as well as in all KOOS subscales  and hs C-reactive protein (hsCRP) with change in total KOOS and several of the KOOS subscale scores. Changes in HbA1c, fasting glucose, and white blood cell were not correlated with changes in total KOOS and its individual subscale scores.p = 0.04) and KOOS ADL  scores, where a decrease in CAF was associated with higher total KOOS and KOOS ADL scores  greater in CCI than UC and greater reduction in both CAF and hsCRP at 2 years were associated with greater likelihood of achieving the MIC  in CCI.At 2 years, 45.5% of the CCI participants and 14.8% of UC participants were classified as total KOOS score ‘improvement”. As an exploratory analysis, the odds of achieving the MIC in total KOOS was 5.4 times , and to identify factors associated with improvement. In this paper, we also conducted sensitivity analysis using pattern mixture-models (PMMs) to assess the issue of missingness in our data and the likelihood of the data missing not at random (MNAR) , 36. MisOur primary analysis results suggest that a medically supervised carbohydrate restricted diet and continuous care intervention statistically and clinically improved total KOOS and all its individual subscores at 1 year and that these improvements are largely maintained out to 2 years among patients with knee pain. In contrast, knee function and pain in the usual care arm did not change significantly from baseline showing a gradually worsening trend commonly observed in patients with T2D , 5, 40. Compared to prior publications, while our analysis demonstrates that weight reduction correlated with improvement in overall KOOS by Pearson correlation, changes in weight alone were not predictive of improvement in overall KOOS by multivariate linear mixed-effects regression. Instead, improvements in CAF and hsCRP were each independent predictors associated with significant improvements in overall KOOS at 2 years. Other studies have demonstrated a strong correlation between weight loss and improved patient reported knee pain and function scores in overweight and T2D patients . The LooWhile many studies have demonstrated improved knee pain with reduced body weight , 16, 19,The strengths of this study are prospective analysis, long term follow-up in a relatively large sample size, and extensive laboratory and anthropometric analysis at multiple time points. Among its potential weaknesses, this is a nonrandomized study performed in a single healthcare system which both represent potential areas for unintentional bias. Therefore, the interpretation of the primary findings was limited to the longitudinal change in total KOOS and its subscores in CCI and UC. The knee score assessment was also limited by the level of missingness in the data. There are potential unmeasured confounders that are not accounted for in the sensitivity analysis and the true missing data trajectory cannot be confirmed from the data. Additional exploratory aims were included to understand the impact of the intervention on knee pain and scores mainly for future study planning. Furthermore, there is an absence of information regarding radiographically confirmed diagnoses of OA in the study subjects. This challenges the direct applicability of our findings to patients with OA as we do not know which of the participants have radiographic OA and which do not. However, given that the causes of knee pain in this population with a high initial BMI are varied and often present in the absence of radiographically significant OA, this study does provide clinical application in that it demonstrates improved generic knee pain and function via a ketogenic diet without regard to an underlying diagnosis.A continuous care intervention including nutritional ketosis was associated with significant improvements in knee pain and function in patients with T2D. While these improvements were observed concurrently with weight loss, this study suggested that the change in knee function were possibly mediated by reduction in central adiposity and inflammation. The findings from this study prompt future research on the applicability of this intervention in radiographically confirmed OA patients.Additional file 1: Supplementary Method Section. Supplementary Table 1. Baseline characteristics of participants with knee pain in CCI and UC and comparison of completers and dropouts or missing data. Supplementary Table 2. Pattern-mixture model sensitivity analysis based on multiple imputation and different MNAR assumption for missing KOOS total and subscores data. Supplementary Figure 1. Patient flowchart from baseline to 2 years with knee score data.


Pharmacological treatments of chronic pain can lead to numerous and sometimes serious adverse effects. Drawing on a social science approach to chronic illness, this study aimed to understand the experiences of people living with chronic pain and community pharmacists regarding the definition, prevention and management of analgesic adverse effects.n = 26) and community pharmacists (n = 19), conducted between July 2020 and February 2021 in the province of Quebec, Canada. The semistructured discussion guides covered participants' definitions of adverse effects and decision‐making regarding their prevention and management. Discussions were audio‐recorded, transcribed verbatim and analysed using grounded theory.This qualitative study proceeded through 12 online focus groups (FGs) with people living with chronic pain (Both people with chronic pain and pharmacists provided varying definitions of analgesic adverse effects depending on patients' social and clinical characteristics. Present quality of life and serious long‐term risks related to treatment were described as key dimensions influencing adverse effect appraisal. Dilemmas and discrepancies occurred between patients and pharmacists when choosing to prioritize pain relief or adverse effect prevention. Some patients lacked information about their medications and wanted to be more involved in decisions, while many pharmacists were concerned by patients' self‐management of adverse effects. Preventing opioid‐related overdoses often led pharmacists to policing practices. Despite most pharmacists wishing they could have a key role in the management of pain and adverse effects face organizational and financial barriers.Defining, preventing and managing adverse effects in the treatment of chronic pain requires a person‐centred approach and shared decision‐making. Clinical training improvements and healthcare organization changes are needed to support pharmacists in providing patients with community‐based follow‐up and reliable information about the adverse effects of chronic pain treatments.A person with lived experience of chronic pain was involved as a coinvestigator in the study. He contributed to shaping the study design and objectives, including major methodological decisions such as the choice of pharmacists as the most appropriate professionals to investigate. In addition, 26 individuals with chronic pain shared their experiences extensively during the FGs. However, most analgesics can lead to adverse effects, which may intensify when several prescribed and/or over‐the‐counter medications are combined.Available data on analgesic adverse effects come primarily from randomized clinical trials, which makes these data difficult to transfer to real‐life experiences.1.2The objective of this study was to understand the experiences and decision‐making of people living with chronic pain and community pharmacists regarding the adverse effects of analgesics. More precisely, the study sought to understand: (a) how, and according to which criteria, people with chronic pain and pharmacists define and classify the adverse effects of pain medications; and (b) how people with chronic pain and pharmacists make decisions to prevent and manage the adverse effects of pain medications in their daily life or practice.The concept of adverse effects used in this study included any unfavourable, unpleasant or harmful outcome following the intake of an analgesic drug or the interaction between an analgesic drug and other medications.This study was based on a qualitative approach to the social experience of chronic illness and the provider/patient relationship, as theorized by interactionist health sociology.2The methods are reported following the Standards for Reporting Qualitative Research (SRQR) recommendations.2.1Centre hospitalier de l'Université de Montréal and the Université du Québec en Abitibi‐Témiscamingue. All participants provided written informed consent by email and all data were anonymized.This was a qualitative study using online (Zoom™) focus groups (FGs) with people living with chronic pain and community pharmacists. Data were collected in the province of Quebec, Canada, between July 2020 and February 2021. The research team conducted six FGs with people living with chronic pain and six FGs with pharmacists. Each FG comprised three to five participants, as recommended in the literature for online FGs.Participants living with chronic pain were recruited in a provincial web‐based prospective cohort study examining pharmacological and nonpharmacological treatments used by adults living with chronic pain.As FG guidelines recommend internal homogeneity of participants,To be eligible, pharmacists had to work in community pharmacies and/or family medicine groups in the province of Quebec. Family medicine groups are multidisciplinary primary care facilities offering services by general practitioners, pharmacists, nurses and/or social workers.Pharmacists were recruited using diverse strategies, including announcements in professional associations' newsletters, websites and/or social media pages, invitations shared in the researchers' professional network and the snowball method. Among the 20 pharmacists who accepted to participate, 19 were finally included (one cancelled participation due to insufficient time). Sociodemographic characteristics of participants are described in Tables 2.2FGs lasted between 90 and 120 min, with a 10‐min break for participants' comfort. FGs were conducted by two experienced research assistants with backgrounds in psychology and sociology. One of them moderated the discussion while the other one observed, took notes and assisted participants with technical issues when needed. Each participant was given a pseudonym to protect anonymity during discussions. FGs were audio‐recorded and transcribed verbatim. Data collection was supervised by the study's principal investigators. After the FGs, participants completed an online sociodemographic questionnaire, and they received CDN $75 for their time.The semistructured discussion guides included open‐ended questions pertaining to participants' definition and management of adverse effects  patients' and pharmacists' experiences and dilemmas while defining, classifying and prioritizing analgesic adverse effects; 2) patients' and pharmacists' practices, expectations and challenges in the management of analgesic adverse effects. A graphical representation of the analytical categories and their dimensions is provided in Figure  patients3.13.1.1Sometimes, I recommend a pain medication and I say, ‘It's going to make you drowsy’. Some patients say, ‘No problem. I'm retired. I'm home all day’. But some others who have to work, who are on the road, truckers, for them it's just impossible. So, their occupation and schedule can make a difference when choosing a treatment. People with chronic pain and pharmacists defined and prioritized adverse effects according to their perspective on the benefit/risk balance of pain medication intake. Participants actively constructed the notion of ‘adverse effect’ through the classification of the different effects as either undesirable/adverse, tolerable or desirable. For both patients and pharmacists, this classification resulted from their individual assessment of medication benefits and risks, which varied according to diverse characteristics, such as the patient's age, comorbidities, professional activity and familial situation. The importance of personalizing the treatment was recurrent in FG discussions. Depending on the patient's situation, a given effect could be alternatively defined as an adverse, undesirable effect or as a desirable, helpful effect. For example, some pharmacists explained that drowsiness was a positive side effect for patients suffering from insomnia, a minor adverse effect for retired patients, while it was concerning for patients with a professional activity requiring productivity or driving:I have fibromyalgia, severe generalized arthritis and emphysema, and the medication allows me to be active. I can go for a walk, I can concentrate enough to read a book, which I wasn't able to do before because of my ADHD [Attention Deficit/Hyperactivity Disorder]. According to several patients, some side effects of their pain medication positively impacted their other health conditions:3.1.2Participants appraised medications' benefit/risk balance through two temporalities: present quality of life and risks for future health. Participants hierarchized adverse effects according to the importance they gave to each of these temporalities in the process of finding an appropriate benefit/risk balance.One of the side effects is that it completely throws off your sleep cycle, so you no longer keep the same hours as everyone else. That complicates your social life and your family life, because you're totally out of the loop, you can't keep up with the others. The impact of adverse effects on their present quality of life was an essential concern reported by most patients. Analgesic adverse effects often affected patients' social, professional and personal living conditions. Patients regretted that some adverse effects interfered with their activities as much as the pain itself. Adverse effects affecting cognitive functions , physical aptitudes  or self‐esteem  were particularly concerning for patients. Several patients were concerned that these adverse effects could be detrimental to their social and familial relationships:We pharmacists can sometimes get concerned about things that patients aren't all that worried about, such as kidney function or long‐term adverse effects. Patients don't necessarily see that aspect. What bothers patients, I think, is whatever affects their quality of life. Some pharmacists reported being committed to reducing the negative consequences of adverse effects on patients' quality of life, which they mainly appraised through functionality . However, among pharmacists, adverse effects affecting patients' quality of life were usually considered of lower priority than those impairing patients' physical health in the long term. Indeed, some adverse effects were mostly invisible but could lead to long‐term serious negative consequences, such as chronic diseases , incapacities  or vital risks . Pharmacists were particularly mindful of these long‐term serious adverse effects that they often found difficult to identify. When they prioritized prevention of irreversible harms over the quality of life, they reported facing some incomprehension from patients:I've done a lot of searching on the Internet and all I found were things from pharmaceutical companies saying you need to take this medication regardless of everything else, even if I end up ruining my liver. They really downplay the number of people who have serious side effects, like liver cancer, and all kinds of other side effects. Nonetheless, adverse effects presenting risks for future health were also deemed concerning by many patients. The perspective of long‐term harms increased patients' uncertainty and powerlessness regarding their prognosis. Many felt they lacked information regarding such serious adverse effects. Some believed that pharmacists, physicians and/or pharmaceutical companies voluntarily hid harmful adverse effects, which highlighted their need to obtain clear information and be involved in their treatment choices:3.1.3I have to take her [an older patient] off one of her pain medications, but then she starts to have pain again because of me. But if I don't remove it, she's going to fall and break her hip. That puts me in an awkward dilemma, it's a choice between having pain or falling and breaking something. FG discussions suggested discrepancies between pharmacists' and patients' views of the importance given to pain versus potential serious harms. Seeking a balance between medication benefits and risks often entailed choosing between pain relief and adverse effect prevention. Many pharmacists insisted on their challenges in dealing with this ethical dilemma:Any adverse effect can lead to stopping the treatment. The good thing, if you like, with pain medications, is that the treatment isn't necessary. For other conditions, heart problems, for instance, there are lots of preventive treatments [that are necessary]. When it comes to treating chronic pain, if the medication doesn't suit the patient, given that the purpose was to relieve pain, to improve quality of life, I have no problem taking them off it. Several pharmacists explained that they could opt for dosage lowering or treatment cessation to limit adverse effects, even though the pain would remain unrelieved. For some of them, analgesics were not deemed ‘necessary’ medications because chronic pain was not a life‐threatening condition:It's not pleasant, but without them [painkillers], I wouldn't be here still. They're my crutch. I really don't have a choice at the moment. My medication is saving my life in a way, despite these problems of discomfort I have to put up with. I need this medication, regardless of the side effects. Some patients too preferred enduring more pain than facing harmful adverse effects. However, for many patients, the affirmation that chronic pain was not life‐threatening was not so evident. Several reported that pain could be so intense that it was hardly tolerable to live with it. They were thus willing to accept intense adverse effects as far as the pain would be effectively relieved:Finally, in many cases, the treatment failed to effectively relieve pain in addition to having adverse effects, leaving patients with a negative benefit/risk balance. Some patients questioned the relevance of taking pain medications under such conditions.3.2FG discussions underscored that the management of analgesic adverse effects took place both in patients' daily living activities and during interactions with prescribers and pharmacists, sometimes generating tensions in the decision‐making.3.2.1I get told off for not taking my painkillers often enough. I try to discuss with my doctors, because you have to weigh the side effects against what you want to do. Yes, I should take it, but I can't follow the doctors' instructions because of the adverse effects, otherwise, I'd have to change jobs, there'd be more impact on my personal life. To reduce adverse effects, several patients reported attempts to self‐manage their pharmacotherapy independently from healthcare providers. This included modifying the dosage or the moment of intake of a prescribed drug, as well as self‐medicating pain or adverse effects with over‐the‐counter and/or natural products. Several patients considered they had progressively acquired skills to manage their pharmacotherapy and better control the impact of adverse effects on their daily living. They claimed expertise for making decisions regarding their treatments . However, patients' experiential knowledge and self‐management practices were often subject to disagreements from physicians and pharmacists. Prescribers were often described as reluctant to involve patients in decisions regarding pain treatments:What I explain to them is, let's say a given product contains 10 different natural products, then obviously with those 10 different things, there's definitely going to be some interactions with the 7 medications you're already taking. So, do what you like, but I'm not necessarily recommending that you take it, and if you do take it, and there's some reaction, then come back and see me again. Many pharmacists, for their part, described the management of adverse effects as negotiations and patient education, rather than shared decisions. They were concerned by patients' other sources of information on their treatments . Several of them insisted on the importance of deconstructing patients' ‘beliefs’ regarding medications and tried to discourage patients' initiatives to modify dosages. Pharmacists were often worried about patients' self‐medication with natural medicine, as they thought patients often underestimated adverse effects and interactions with other drugs. They found it challenging to obtain information from patients regarding these practices and tried to educate them about potential harms while maintaining the dialogue:I used to work in health care, and my anaesthetist at the pain clinic leaves me lots of latitude to manage my medication, so I have a major advantage in being able to self‐manage it. I'm the one who tells him: ‘Prescribe me more of that’ or, ‘I stopped taking that’. However, some patients described physicians and pharmacists accepting shared decision‐making. Having professional experience in the healthcare field was reported as a facilitator to obtain providers' recognizing of their experiential knowledge as patients:My orthopaedist, when I last saw him, he said, ‘Do you need more?’ So, am I the one who decides? And the pharmacist suggests but doesn't impose anything. So, I'm the one who's managing my medication. I could have far more than I'm getting at the moment, but I think I'm already taking quite a lot. There's no one putting the brakes on for me. I'm the one making the decision, it's a little sad, but that's the way it is. Other patients felt unsatisfied with the self‐management of their pharmacotherapy, especially when they perceived it as the result of insufficient involvement of providers rather than their own choice. These participants felt left alone with medication‐related risks and adverse effects, as for this patient treated with opioids:3.2.2The first thing she [my new pharmacist] did was to report me to the College of Pharmacists, claiming I was a drug dealer. In her mind, it was impossible for someone to take so many drugs and still be able to walk and talk. In the case of opioid treatments, pharmacists reported that their involvement in the management of adverse effects often took the form of monitoring and policing patients' medication use. Several patients using opioids for their chronic pain were concerned that pharmacists could suspect them of nonmedical use, and threaten the continuity of their treatment:As far as dependency goes and managing opioids, if you say to them, ‘No, I can't serve you today. You've still got some left at home’, then the person comes up with excuses. So, you might believe them the first time, but at some point, it's no longer acceptable. You have to set dates, to demand that people bring their medications into the pharmacy to see what they have left. All that kind of thing is really no fun. All that policing side of it, that can be really annoying sometimes. Several pharmacists believed that the ‘police officer’ role was part of their missions with patients using opioids for chronic pain, though some of them disliked these tasks that were at the boundaries of healthcare:We pharmacists have the means to give out a kind of opioid EpiPen® called naloxone, so that patients can have it at home if they overdose on their opioids. So, if, for some reason, because they were in pain, they've taken a little more than they should have, and they have a breathing arrest, they can take naloxone. But getting patients to give this solution a try is a whole new challenge, because when you suggest it, they say, ‘I'm not a drug addict. I take medication to relieve my pain, but I'm not a junkie living on the street, so I don't think I need that’. It's really stigmatized. Furthermore, opioid overdose prevention could cause challenging dialogue between patients and pharmacists. Naloxone, for example, was seen by several pharmacists as an important tool to reverse the effects of overdoses. However, patients facing opioid‐related stigma in their daily life were not likely to accept naloxone because they felt negatively labelled as opioid‐dependent or recreational consumers:3.2.3It's really important to follow up with the patient because some side effects are temporary and sometimes, just getting a bit of encouragement to keep going will help the patient to continue long enough to see the benefits. Many pharmacists considered they had, or should have, a key role to play in the management of analgesic adverse effects, including patient follow‐up, treatment optimization, patient education and support:Most of the time, I talk to my pharmacist because she knows more than the doctor about chronic pain. I learned from her that that there can be a serotonin effect between two medications that wouldn't normally be combined for the same patient. My doctor didn't know that much about it, and she didn't care that much either because we're talking about rare side effects, so I wasn't supposed to have them. But I did have side effects that were related to that. So, my pharmacist's expertise was better than my doctor's. Several patients viewed their pharmacist as an easily available expert on medications, more competent than physicians in addressing their problems with analgesic adverse effects:I have no relationship with pharmacists. I pick up my medication or have it delivered but I don't talk to anyone. I pay and that's it. The pharmacist's there to make sure the pills are okay but I have no relationship. I talk with the cashiers, with the technician who comes to fetch the prescriptions, that's all. However, other patients described pharmacists as medication retailers only. They did not recognize in them specific expertise. Several patients deplored that pharmacists were not likely to provide information on adverse effects unless patients took the initiative to ask. In addition, some reported having no discussions with pharmacists at all:If someone comes and makes an appointment, we're not compensated for that. At present, the system doesn't operate on a fee‐for‐service basis, but rather on the basis of the volume of renewed prescriptions, so profitability depends on volume. We're not paid for a pharmacotherapy follow‐up of a patient, that's where the problem lies. Tensions between the role of community healthcare providers and the role of the business owners were omnipresent in pharmacists' discussions. Many of them explained that in an ideal world, they wished they could be highly involved in the management of adverse effects of chronic pain medications, through in‐depth one‐on‐one appointments with patients. However, many pharmacists described barriers related to insufficient time, lack of space and inappropriate remuneration policies in community pharmacies, which led them to prioritize fast medication delivery instead of close patient follow‐up:For pharmacists working in family medicine groups, such constraints were less intense though time‐related barriers remained omnipresent.4The original contribution of this qualitative study was to provide an in‐depth understanding of the experience and management of analgesic adverse effects from the double perspective of chronic pain patients and community pharmacists. This study included all types of analgesic drugs while previous studies in the field focused on one single type of medication, usually opioids, and were mostly physician‐centred. Below, we discuss the study's most significant scientific contributions and practical implications regarding person‐centred care and shared decision‐making, and we suggest novel avenues to foster pharmacists' involvement in managing chronic pain pharmacotherapies and associated adverse effects.This study showed that both patients and pharmacists constructed the benefit‐risk balance of adverse effects based on each patient's social and clinical characteristics. A given effect could be considered both an adverse effect by/for one patient or a beneficial effect by/for another patient. Participants highlighted the relative and variable nature of adverse effects according to patients' socioprofessional activities, age and comorbidities. This original finding testifies to participants' personalized approach to adverse effect prevention and management. This finding reinforces the relevance of person‐centred approaches to the management of pain in primary care.In this study, the process of prioritizing adverse effects was not without its dilemmas for patients and pharmacists. Another qualitative study held in the general population described the benefit‐risk balancing of patients choosing between disease‐ and treatment‐related risks in the process of treatment initiation.With the view of fostering shared decision‐making, it is essential that pharmacists, and, more generally, health professionals, provide patients with information and support to make evidence‐based decisions about treatments and adverse effects.In the case of opioids, stigma played an important role in both patients' and pharmacists' experiences. Stigma experiences in various healthcare environments, and feelings of losing control of decisions regarding opioid therapies are frequent among patients treated with opioids for chronic pain, especially in the context of current opioid‐policy changes.This study underscored the important role of pharmacists as easily accessible healthcare professionals for providing patients with information, monitoring and interventions regarding pain medications and adverse effects. Several other studies in the general population noted that pharmacists' availability was one major factor fostering patients' trust in their advice and the development of a sustainable relationship.Indeed, several pharmacists in our study reported healthcare system‐related barriers to their involvement in the management of analgesic adverse effects. Their remuneration system forced them to prioritize high volumes of medication delivery, thus hindering their ability to make in‐depth follow‐ups. A Canadian study underscored that financial factors were among the barriers preventing community pharmacists from taking part in the multidisciplinary treatment of chronic pain, as these pharmacists were dissuaded to seek nonpharmacological alternatives.Regarding study limitations, as shown in Table 5This study advanced knowledge by showing the complexity of defining, prioritizing and managing the adverse effects of chronic pain medications, as well as the dilemmas and discrepancies that adverse effect management can create in the patient–pharmacist relationship. With the vision of fostering patient‐centred management of adverse effects and shared decision‐making, it is essential to improve pharmacists' training in pain management, and to support them in delivering accurate information to their patients about analgesics and their adverse effects. Policy efforts need to be made to provide pharmacists with adequate material resources to play their critical role as primary care experts of pharmacological therapies.The authors declare that there are no conflict of interests.Centre Hospitalier de l'Université de Montréal and the Université du Québec en Abitibi‐Témiscamingue have reviewed and approved this study (No. 19.367). All participants provided written informed consent to participate.The Research Ethics Committees of the The principal investigators in this study are Lise Dassieu and Emilie Paul‐Savoie. Lise Dassieu led the study, contributed to study design, recruitment, data collection supervision, data analysis and drafted the manuscript. Emilie Paul‐Savoie contributed to study lead, study design, recruitment and revised the manuscript. Elise Develay contributed to study administrative coordination, recruitment, data collection, data analysis and manuscript revisions. Ana Cecilia Villela Guilhon contributed to data collection, data analysis and manuscript revisions. Anaïs Lacasse and Line Guénette contributed to study design, recruitment and manuscript revisions. Kadija Perreault, Hélène Beaudry and Laurent Dupuis (person with lived experience) contributed to study design and manuscript revisions.Supporting information.Click here for additional data file.Supporting information.Click here for additional data file.