Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by mutations in the SMN gene, leading to progressive muscular weakness, atrophy and so far neglected musculoskeletal pain. This study is the first to characterize nociceptive pain in patients living with SMA type 3 by assessing whether muscle pain is associated with alterations in muscle strength, function, stiffness, frequency, decrement, relaxation, or creep.®). For statistical analysis, we used t tests, Mann–Whitney U tests and linear regression.We performed a cross-sectional pilot study on 20 SMA3 patients. We evaluated motor function and muscle strength , nociceptive pain ) and non-invasive measurement of muscle stiffness, frequency, decrement, relaxation, or creep (myotonometry with the MyotonProp = 0.003). A lower score in dynamometry was associated with lower scores in PPT in all extremities reflecting a higher sensitivity of these muscles to pressure. We did not find significant correlations between the PPT values and the MyotonPro values in the corresponding muscles. Assessments of PPT before and after the 6-min walk test did not show clinical meaningful changes. Besides nociceptive pain, fatigue was prevalent in 50% and pain in 55% of the patients.Significantly more women than men reported musculoskeletal pain (Muscle pain in SMA3 is associated with muscular weakness in the arms and legs, but not with changes in muscular stiffness, frequency, decrement, relaxation, or creep. This shows that muscle pain in SMA3 is mainly caused by changes in the dysbalanced musculoskeletal system due to muscle weakness.The online version contains supplementary material available at 10.1007/s00415-022-11351-0. Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disorder caused predominantly by a homozygous deletion  of the SThe prevalence of pain and fatigue is estimated between 30 and 90% in all types of neuromuscular diseases . MusculoThis explorative, cross-sectional clinical study aimed to characterize the prevalence, quality, intensity and distribution of musculoskeletal nociceptive pain, and fatigue in adult patients with longstanding SMA3. The second objective was to assess whether muscle pain severity and distribution are associated with alterations in muscle function, muscle strength and muscle stiffness or elasticity. Only adult patients aged ≥ 18 years with genetically confirmed 5q-SMA, clinically type 3/walkers and ability to perform study-related functional tests were enrolled in this study. Because of possible interference between depressive symptoms and pain, patients with a Beck Depression Inventory-Fast Screen score > 3 were excluded from study participation. Other exclusion criteria were participation in another clinical study, use of an investigational treatment, or inability (in the investigator's opinion) to adhere to the requirements of the study. All patients were enrolled at the neuromuscular expert center Friedrich-Baur-Institute at the LMU Munich, Germany. The study was approved by the ethics committee of the LMU Klinikum, Project No. 20–0980, and the protocol was registered on a public clinical trials registry .Musculoskeletal strength was assessed by the MRC scale  and dynamometry. Muscle strength was assigned an MRC score with a range from 0 (no movement possible) to 5 (maximum force) for each muscle . Dynamom2 and the stimulus intensity was increased until the patient felt any sensation of pain. The result was taken in kg as the arithmetic mean of three repeats and was recorded on both sides of the trapezius, deltoideus, supraspinatus, biceps brachii, rectus femoris, tibialis anterior and gastrocnemius muscles, as well as the erectors spinii and the neck extensor muscles.A pressure algometer was used as a reliable method to quantify local pain by measuring the musculoskeletal pressure pain threshold (PPT) in different muscles. The algometer was placed onto the muscles with a contact area of 1 cmM. rectus femoris and M. gastrocnemius) before and after the 6MWT and evaluating pain symptoms during the test. The QMFT is widely used in assessing neuromuscular diseases, delivering a score of movement and muscle function from 0 to 64 points [A 6-min walk test (6MWT) and a Quick Motor Function Test (QMFT) were performed to examine the physical function and muscular endurance. The 6MWT  was adap4 points .®. The tip of the MyotonPro® is placed perpendicular to the underlying muscle. A slight pressure with a constant preload induces an oscillation, which leads to a short-term deformation of the underlying muscle. An acceleration sensor now analyzes the vibration behavior of the muscle and the viscoelastic stiffness is calculated. The calculation is based on the stiffness of the muscle (in N/m), the elasticity  and the duration required for this. Values of the MyotonPro were assessed for the neck extensor muscles, the trapezius, supraspinatus, deltoideus, biceps brachii, erectors spinii, rectus femoris, tibialis anterior and gastrocnemius muscles on both sides. The MyotonPro® was rated as having an excellent test–retest reliability for most muscles [For the non-invasive measurement of muscle stiffness, muscle tone, muscle relaxation and viscoelasticity, myotonometry was performed using the commercially available MyotonPro muscles , but was, spinal muscular atrophy type 2 and congenital myopathies [The characteristics of both pain types were explained to the patient to differ between nociceptive and neuropathic pain. Pain that could not be assigned to nociceptive pain  was also captured in the study. Before the clinical examination, disease-related history, medical history and disease- and quality-of-life-related questionnaires  were obtained. Historical data were collected with a focus on the intensity, frequency, and quality of nociceptive pain and previous and current drug use or non-drug therapy methods  and surgery influencing the myalgia. The Fatigue Severity Scale (FSS) includes nine questions and evaluates the severity of fatigue, i.e., physical and mental exhaustion and its influence on the quality of life. The FSS total score is the average of the nine-item scores and ranges from 1 (“no signs of fatigue”) to 7 (“most disabling fatigue”). For this study, a cutoff value greater than four was chosen for evaluating the presence of fatigue . The FSSopathies . The Briopathies . The paiopathies  and is iopathies .A detailed description of pain was evaluated with the German Pain Questionnaire (GPQ), including pain sites, duration, intensity, pain-relieving and -aggravating conditions and subjective pain perception . The GPQThe DASS  is a brief and reliable questionnaire . The queThe Marburg Questionnaire (MFHW) was used to assess habitual well-being in relation to perceived pain. It consists of seven questions regarding mental, physical and emotional well-being and performance despite the experienced pain. It provides additional information compared with the DASS by addressing positive abilities of the patients. The maximum score is 35 points, indicating a particularly high level of well-being. A score of ten points and below is a low value of habitual well-being in pain patients.A detailed description of pain was evaluated with the German Pain Questionnaire (GPQ), including pain sites, duration, intensity, pain-relieving and -aggravating conditions and subjective pain perception . The GPQ® Version 27 and Microsoft Excel® 2016 were used for the analysis. For the illustrations of the human body, BioRender® was used. All data were graphically checked for normal distribution. For all metric, normally distributed values, we performed an unpaired, two-sided t test. For all non-parametric values, we performed a Mann–Whitney U test. For the change in PPT values before and after the 6MWT, we performed a paired two-sided t test or a Wilcoxon rank test. The significance level  was set at ≤ 0.05.SPSS StatisticsAll patients gave written informed consent before the first assessment. Of 25 patients screened for eligibility, 20 patients were enrolled in the study. Two patients declined to participate after study information, and three patients were not eligible due to a score of ≥ 4 in BDI-Fs at screening. Because of the significantly different perceptions of pain in men and women Table , we divip = 0.003). Two patients (26.8%) took pain medication irregularly as needed due to muscle pain. The pain was chronic (experienced for longer than 6 months) in ten patients. The pain was only nociceptive in six patients and mixed in five patients. All patients received nusinersen as a specific disease treatment. 13 (65%) patients were ambulant and could perform the 6MWT. In seven (35%) patients who were either wheelchair dependent or only able to walk a few steps, the 6MWT was not performed. There was no significant difference between men and women in any category regarding muscle strength, muscle function (assessed by the QMFT) or fatigue.Baseline demographics are provided in Table Prevalence of fatigue (FSS score > 4) was high within the cohort  and was present in six male (46%) and four female (57%) patients.n = 11) of the SMA patients reported nociceptive or mixed pain with a high localization and strength variability, visualized in Figs. n = 9, 81.8%), and only two patients reported permanent pain (18.2%). Overall, the pain was perceived in declining frequency in the lumbar spine region (54.5%), the legs, especially in the knees (45.5%) and in the neck (27.3%).55% n = 1 of the p = 0.003; Table Women with SMA experienced pain significantly more often . To relieve the pain, most patients chose relaxation, for example, going for a walk or resting . In general, movement and exercises were associated with pain triggers and pain relievers. Two female patients used pain-specific treatment: both took ibuprofen 600 mg as needed up to four times a month. One female patient tried massage and hot baths for pain relief, but with only minimal benefit.Pain triggers are summarized in Table All patients received nusinersen as disease-specific treatment at baseline , which was no longer evident after Bonferroni correction . Figure Pain pressure threshold (PPT) was lower in women than in men in nearly all muscles Fig. . Howeverp = 0.041*) and the leg region (p = 0.024*), especially for the distal part (p = 0.022*), but not for the shoulder and neck region or for the trunk region , legs , shoulder and neck region  and trunk (erector spinii muscles) Table . We alson p = 0.04*, espec® are presented in Table ® parameter, such as frequency, stiffness, decrement, relaxation and creep, only the PPT of the rectus femoris on the right side correlated negatively with its decrement . The regression model was not significant .Correlation with the parameters of the MytonProp = 0.034), and further analysis using Cohen’s d suggests a high effect size (d = 0.79).Results of the adapted 6MWT in 13 patients are shown in Table Despite the relatively high number of SMA patients regularly seen at the neuromuscular expert centre, only a small number of patients were eligible or consented to participation in this study, making a comprehensive statistical analysis of factors influencing nociceptive pain not reasonable. On the other hand, this is the first study in a sufficient number of patients with longstanding SMA3 evaluating nociceptive pain by combining results from clinical assessments, medical history and pain-related questionnaires.We conducted this pilot study of nociceptive pain in longstanding SMA 3  patients, which is the first to our knowledge that combines results from medical history, clinical assessments and pain-specific and health-related patient-reported outcomes. In summary, muscle pain in SMA3 is reported by approximately 50% of the patients and musculoskeletal dysbalance due to regional muscle weakness seems to be the underlying cause. Due to our findings, muscle pain is associated with muscular weakness in the arms and legs, but not with changes in muscular stiffness, frequency, decrement, relaxation or creep.p = 0.037; supplements). Besides, we found an association between muscle strength and algometer scores of the arms and legs in the linear regression model (Table Measurements of pressure pain threshold (PPT) were lower in women than in men in nearly all muscles, indicating a higher susceptibility of pain perception in women. In healthy volunteers, examinations  showed tel Table , especiaAssessments of pressure pain threshold (PPT) before and after the 6-min walk test, which reflects a standard test for muscular endurance in neuromuscular disorders, did not show valuable or clinical meaningful change. Of the cohort, only two women complained of muscular pain after the 6MWT. Besides, patients reported a way of pain relief due to muscle exercise, but also a high number complained about muscle pain after too much exercise and physical exertion. Only two female patients used pain-specific medication. Although conclusions should be made very carefully due to the small sample size, our results do not indicate that muscle endurance activity measured by the 6MWT induces muscle pain or lowers the pain threshold. As reported by patients, muscular endurance exercises may be more beneficial for pain reduction than provoking pain, as long as muscles are not overstressed. Overall, further research is necessary for the efficacy of muscle training in SMA patients to prevent muscle wasting and muscle pain and maintain muscle strength as long as possible.p = 0.044, correlation coefficient = − 0.349; R2 = 0.135). PPTs of the rectus femoris muscle decrease with higher decrement values equivalent to lower elasticity values . Elasticity is a measure of the muscle’s ability to recover its initial shape after deformation. The lower elasticity of the muscle, the lower the PPTs.We did not find correlations between the PPT values and the MyotonPro values for frequency, stiffness, decrement, relaxation and creep in the corresponding muscles. The only statistically significant correlation was found between the PPT of the rectus femoris on the right side and the decrement of the right side , but could not explain the high proportion of low back pain in women.Comparison with results of previous studies is difficult to make, as most of them were questionnaire based and none included objective clinical assessments. A survey from de Groot et al.  summarizEven though a potential effect on pain of nusinersen was not a predefined outcome, our data suggest that there is no relevant impact on the occurrence or frequency or intensity of pain, which might be due to a relatively short-term specific therapy in longstanding chronic disease. But further particular studies are needed to evaluate the effect of SMA specific therapies on nociceptive pain.Overall, muscle pain in SMA type 3 cannot be explained by changes in muscular stiffness, frequency, decrement, relaxation or creep. This shows that muscle pain in SMA type 3 is mainly caused by changes in the dysbalanced musculoskeletal system, caused by  muscular weakness. As our conclusions are based on a relatively small cohort, we suggest evaluating pain in SMA3 in larger cohorts in the future.Supplementary file1 (DOCX 18 KB)Below is the link to the electronic supplementary material.


Trigeminal neuralgia is an episodic severe neuralgic pain and can be managed both medically and surgically. If possible, this should be directed by a Multidisciplinary Team (MDT) of specialised surgeons, physicians, dentists, psychologists and specialist nurses with access to all treatment modalities, which enables patients to make an informed decision about their future management.The aim of this study was to review the outcomes of patients managed by an MDT clinic, in a single institute over an eleven-year period.A prospective database was used to identify patients with trigeminal neuralgia or its variants who had attended a joint MDT clinic. The electronic notes were examined for demographics, onset and duration of trigeminal neuralgia, medications history, pain scores and details of surgical procedures if any by two independent assessors.Three hundred thirty-four patients attended the MDT between 2008–2019. Forty-nine of them had surgery before being referred to the service and were included but analysed as a subgroup. Of the remaining patients, 54% opted to have surgery following the MDT either immediately or at a later date. At the last reported visit 55% of patients who opted to have surgery were pain free and off medications, compared to 15.5% of medically managed patients. Surgical complications were mostly attributable to numbness and in the majority of cases this was temporary. All patients who were not pain free, had complications after surgery or opted to remain on medical therapy were followed up in a facial pain clinic which has access to pain physicians, clinical nurse specialists and a tailored pain management program. Regular patient related outcome measures are collected to evaluate outcomes.An MDT clinic offers an opportunity for shared decision making with patients deciding on their personal care pathway which is valued by patients. Not all patients opt for surgery, and some continue to attend a multidisciplinary follow up program. Providing a full range of services including psychological support, improves outcomes. Trigeminal neuralgia (TN) is an episodic severe neuralgic pain, primarily unilateral, affecting the trigeminal nerve and resulting in significant impact on quality of life . By far,TN can be successfully managed medically. Patients with medically refractory TN or who cannot tolerate medications due to side effects can be managed surgically. Recently updated guidelines support both forms of management . PatientA long-term follow-up study of a mixed cohort of patients showed that 40% end up having surgery, and the remainder obtain reasonable control of their TN using a range of medical therapies .Not surprisingly, it has been demonstrated that a multi-disciplinary approach to managing patients with TN results in better outcomes . In thisIn this study, we aim to present long-term experience from a single centre of managing patients with TN in a joint Multidisciplinary Team (MDT) clinic over eleven years.https://www.brainandspine.org.uk/our-publications/booklets/face-pain/) [https://www.tna.org.uk/ [The joint neurosurgical MDT clinic for TN is attended by one or more of three specialised neurosurgeons and a physician consultant who is both medically and dentally qualified. It is held once a month with a maximum of six patients attending with a partner or a carer. Prior to attending, all patients undergo meticulous phenotyping by a physician as well as a battery of assessment including a brain MRI with cranial nerves sequences to visualise the trigeminal nerves. Patients are also requested to complete a set of patient related outcome measures at each visit. The diagnosis and MRI findings are reviewed and confirmed by the MDT. The pertinent surgical options , are offered to patients provided there are no contra-indications e.g., medical morbidity. Patients who wished to have stereotactic radiosurgery were warned that pain relief would not be immediate, and that this was therefore potentially not suitable for those with poor pain control, but more suited to those who had manageable pain, or were pain free and had significant side effects with medication. All patients had access to a pain management program which included clinical psychologists and physiotherapist , 11 as we-pain/) , and a ce-pain/)  is provi.org.uk/ . DependiA prospective database of all patients attending the MDT clinic is maintained and from this the sample was chosen. Outcomes for this study were assessed by reviewing of the electronic medical records by two independent observer . Patients who attended the MDT clinic over a period of eleven years (2008–2019) were evaluated.All patients who would potentially benefit form a neurosurgical procedure. These included patients with classic TN, idiopathic TN, TN secondary to multiple sclerosis with or without concomitant pain. A small number were later reclassified as having, short unilateral neuralgiform pain with autonomic symptoms, short unilateral neuralgiform pain with conjunctival redness and tearing.as their autonomic symptoms were present consistently. The International Classification of Headache Disorders criteria was applied to making the diagnosis . PatientPatients with secondary TN due to tumours, cysts, arteriovenous malformations or other types of facial pain e.g., temporomandibular disorders, trigeminal neuropathic pain, and glossopharyngeal neuralgia. Patients with incomplete or inaccessible records and patients who were lost to follow up after opting for surgery were excluded.An MDT clinic database kept prospectively, was used to identify eligible patients before reviewing the electronic records. These included outpatient letters and operating notes. The following information was extracted: demographics, source of referrals, duration of trigeminal neuralgia, pain status and drugs used , and the type and total number of surgical procedures patients underwent. Complications were classified according to Landriel-Ibanez model .Pain free: no pain, no drugsPain free on drugsPain mild: 1–3/10 – odd twinge now or in last six months daily or only some days, low dose drugsPain moderate: 4–7/10, regular pain attacks daily but can cope on drugPain severe: 8–10/10– every day, frequent attacks, having to eat soft food, high dose drugsPatient reported outcome measures (PROMS) from questionnaires had not been digitised by the time of this study and were therefore not included. Pain status was therefore assessed from the letters which include only a summary of the PROMS but allow for the following grading:Descriptive statistics were presented for patient characteristics by the type of medical and surgical management they underwent. Frequency and percentages were used for categorical variables and mean (standard deviation) was used for continuous variables. The difference between groups was investigated by two-sample t-test, or ANOVA for continuous variables and chi-squared test for categorical variables.This was a service evaluation and so patient consent and ethical approval was not required.The diagnosis of those in the study is shown in Fig. The basic demographics are shown in Table n = 285), a higher proportion opted to have surgery 153 (54%) versus 132 (46%) who opted for medical management only. At the last reported visit of the medically managed patients, only 18 patients (15.5%) were pain free and off drugs with a further 10 patients (8.6%) reporting no pain but on drugs. Whereas in the surgical cohort 84(55%) were pain free and off drugs and a further 20 patients (13%) pain free on drugs.Of the group of patients who have not had a surgical procedure prior to the MDT clinic  had a different procedure. In this group, three patients (43%) had radiofrequency thermocoagulation, two patients (28%) had glycerol rhizotomies and two patients (28%) had an MVD. None of the MS patients had an MVD with 6 (86%) in this group either having a glycerol rhizotomy or radiofrequency thermocoagulation. Two patients had initially failed glycerol rhizotomies due to technical difficulties.Up to 14% attended another MDT clinic appointment before making their decision. Of the patients who opted for surgery, the most commonly chosen procedure was microvascular decompression (61%) as shown in Table Follow up data was available on 145 of 153 (94.8%) surgical patients. The reasons for lost to follow up was due to: five patients did not have computer records available for the last visit in the service, one patient was lost to follow-up, one patient had recent surgery at the time of data collection, and one patient decided to have the surgery done in another hospital privately. The complications after the differing surgical procedures are shown using the Landriel-Ibanez classification  in TableOf the 49 patients who had surgery before coming to an MDT 26 patients 53)% did not require further surgery as shown by Table 3% did noIn this study, we looked at long-term outcomes of a large cohort of TN patients attending an MDT clinic with both surgeons and physicians being present at the same time with additional structured support of a facial pain team. All data were extracted and analysed by independent assessors .https://www.rcseng.ac.uk/dental-faculties/fds/publications-guidelines/clinical-guidelines/) [Fifty four percent of patients with no history of previous procedures opted to undergo surgery, which is in support of the decision analysis study by Spatz et al. , where telines/) .The pathway used by our team follows the same pathway as described by Heinskou et al.  but in tThere is a considerable delay before patients are referred to specialist centres where there is an agreed care pathway with access to an MDT . This paThe complication rate for all surgical procedures appears excessively high. However, the great majority are accounted for by numbness, much of which was temporary, which could be argued is an expected result of trigeminal destructive procedures. Very few patients reported numbness to be severe, long lasting, and intrusive. Three patients reporting hearing problems were not thought to be related to the procedure, but due to prior problems. The rate of CSF leak following MVD is high (17%) but remains in keeping with various reviews reporting an incidence between 0–22% . A changThere is a need to increase awareness among health care professionals and TN patients of positive outcomes, and that not all patients need surgery to achieve pain control. Nevertheless, patients should be offered the full range of options at an early stage and be referred to specialist centres. The UK NICE guidelines on management of neuropathic pain including TN suggest that patients with TN should be referred to specialist centres once carbamazepine has failed . This atSome studies have examined cost effectiveness of neurosurgical procedures, but only one small study comparing medical management versus MVD . Lemos eSome patients were lost to follow up after the MDT. Patients are discharged six weeks after successful surgery, so we cannot be sure that all patients maintained their good outcomes. Although recording of Patient Reported Outcome Measures (PROMs) was carried out, these were not scanned into electronic records, and it was not possible to retrieve all the paper notes. PROMS were very important in making decisions about further management. The Liverpool Adverse Events profile  helped tAn MDT clinic with both physician and surgeon in which patients are seen after initial work up provides an opportunity for patients to decide on their personal care pathway which can be altered over time, and which includes support from a multidisciplinary team.


Background: The increase in the medical use of cannabis has revealed a number of beneficial effects, a variety of adverse side effects and great inter-individual variability. Association studies connecting consumption, addiction and side effects related to recreational cannabis use have led to the identification of several polymorphic genes that may play a role in the pharmacodynamics and pharmacokinetics of cannabis. Method: In total, 600 patients treated with cannabis were genotyped for several candidate polymorphic genes , encoding receptors CNR1 and TRPV1; for the ABCB1 transporter; for biotransformation, bioactivation and biosynthesis; and CYP3A4, COMT and UGT2B7 conjugation. Results: Three polymorphic genes  were identified as being significantly associated with decline in pain after treatment with cannabis. Patients simultaneously carrying the most favourable allele combinations showed a greater reduction (polygenic effect) in pain compared to those with a less favourable combination. Considering genotype combinations, we could group patients into good responders, intermediate responders and poor or non-responders. Results suggest that genetic makeup is, at the moment, a significant predictive factor of the variability in response to cannabis. Conclusions: This study proves, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain management and side effects, including therapy dropout. Significance: Our attention to pharmacogenetics began in 2008, with the publication of a first study on the association between genetic polymorphisms and morphine action in pain relief. The study we are presenting is the first observational study conducted on a large number of patients involving several polymorphic candidate genes. The data obtained suggest that genetic makeup can be a predictive factor in the response to cannabis therapy and that more extensive and planned studies are needed for the opening of new scenarios for the personalization of cannabis therapy. The therapeutic use of cannabis dates back to 2800 B.C. in China, and its diffusion in Europe to treat various diseases occurred mainly in the 18th and 19th centuries ,4 and grAn “open-label”, multi-centric, non-randomized observational study to assess the feasibility of possible associations between the outcomes of treatment with cannabis in patients suffering from chronic pain, for different diseases and certain polymorphic candidate genes.In total, 600 Italian patients of Caucasian origin, undergoing cannabis therapy for chronic pain, were recruited by Azienda USL Toscana Sud-Est, Zona Arezzo, San Donato Hospital , Department of Pain Medicine and Palliative Care, starting in 2018. The study was approved by the Tuscan Regional Ethical Committee (n. 1287) in 15 May 2018. None of the patients refused to take part in the project, reaching a total participation rate of 100%.Patients were informed of the project and gave written consent to participating in the study and permitting their genotyping. They were interviewed and assessed for pain severity, in addition to collecting information on their age, sex and pain treatment. Exclusion criteria: age below 18 years, organic or psychiatric disorders interfering with judgement and comprehension abilities, persistence of pain for less than three months, no treatment with painkillers from traditional pharmacopoeia, pregnancy or breast-feeding, arrhythmia or ischemic cardiopathy, patients with severe psychiatric disorders, patients with a history of abuse or addiction to cannabis or other psychoactive substances.Inclusion criteria: chronic pain, use of painkillers from traditional pharmacopoeia for at least three months without complete efficacy, full ability to understand.Procedures were compliant with the ethical rules of the committee responsible for human experimentation and with the 1975 Helsinki Declaration, as reviewed in 2008.Patients were grouped into five categories based on the type of disease originating the pain: (1) central nervous system diseases; (2) rheumatoid, arthritic, inflammatory and autoimmune diseases; (3) headache and migraine; (4) neuropathic pain; (5) cancer pain.(1)Pain intensity measured with the visual analogue scale (0–10);(2)Presence/absence of benefits ;(3)Presence/absence of side effects ;(4)Anxiety and depression symptoms, measured with the hospital anxiety and depression scale (HADS) .Interviews and data collection were carried out during the first examination (T0), after 4 weeks (T1) and after 12 months. During the study, a few patients decided to drop out of therapy, either because of unresponsiveness to cannabis therapy or because of relevant side effects. Measured variables were, mainly:® , Cannabis FlosBedrolite® , Cannabis FlosBediol® , Cannabis FM2®  and Cannabis FM1® . The different preparations of cannabis inflorescence were extracted in accordance with the SIFAP  method [Administered cannabis preparations were: Cannabis FlosBedrocan) method , CannabiMDR1/ABCB1 rs1045642; TRPV1 rs8065080; 5-UGTB7 rs7438135; CYP3A4 rs2242480; CNR17B rs1049353; COMT rs4680.Genetic variants  in candidate genes were selected from previous publications with at least one positive association with a proven biological activity in individuals using cannabis for recreational purposes, given the lack of suitable indications in patients using cannabis for medical purposes. The 6 selected SNPs were: The DNA was obtained with an oral swab and extracted with DNA Extract All Lysis Reagent , and SNPs were determined with TaqMan Assay (Applied Biosystem) with an RT-PCR One-Step-Plus system (Applied Biosystem by Thermo Fisher).The main dependent variable was pain reduction (∆VAS), calculated as the difference between basal pain and the pain assessed in each subsequent time. Each patient, therefore, also represented their own control. A multi-variate linear regression model (MLR) was used to assess the significance of the effect of variables on ∆VAS: year and centre of recruitment, age, gender, genotype, disease, painkillers and medication taken, type of cannabis and THC and CBD doses. The χ2 test and/or multi-nomial logistic regression were used for associations between categorical variables and the Kruskal–Wallis t (K–W) test for non-normally distributed variables. Associations with genotypes were initially tested within a co-dominant inheritance model (three separate genotypes). Simplified models were then applied: a dominant model  and a recessive model  when effects were not significantly different. Being an explorative study, Bonferroni correction was not applied. All statistical analysis have been performed by Stat Graphics Centurion XVI, by Statgraphics Technologies, Inc. The Plains, VA, USA.p < 0.05). The allelic proportions of the genes considered did not vary significantly in different disease groups or according to the different types of cannabis used. Patient demographics are reported in Out of 600 patients recruited in the study, 564 were eligible for the analysis, as there was a complete database including correct genotyping. For the genotype quality control, a Hardy–Weinberg (H–W) equilibrium test was performed; all genotypes tested statistically in the H–W equilibrium  and of CBD , despite doses having doubled overall.Pain reduction was approximately 20% in the first month, subsequently reducing by half in the third month and then further decreasing to 43% after one year. During the whole study, 443 patients (75.7%) dropped out of cannabis therapy, 179 of them putting forward various reasons, such as poor or no pain reduction, side effects or both, whereas the reasons for the remaining 264 were unknown. Polymorphism frequencies did not change significantly as a result of the drop-out factor. A decrease in ∆VAS during the first month was not significantly correlated with doses (squared) of THC , only polymorphisms for the ABCB1 , as displayed by p < 0.05).The MLR (multi-variate linear regression) analysis of ∆VAS showed a highly significant effect in new groupings . Consequently, we concluded that the poor responders to cannabis were patients carrying three non-favourable alleles.Patients were further grouped based on the amount of favourable allele combinations for each genotype: group one with two or three favourable alleles, i.e., CC + CT for p < 0.05) different pain decreases. Group three, therefore, showed a 0.56 ∆VAS, classifying Group three as non-responders. Group two showed a 1.29 ∆VAS—that is, 2.3 times higher than group three—and could be considered to constitute responders. Group one showed a 1.73 ∆VAS—that is, 3.1 times higher than group three—and could be considered to have the highest number of responders.Patients grouped on the basis of their genotypes being more or less favourable to a pain decrease could be classified in groups with statistically significantly , with a larger proportion of women .At the beginning of the study, 98 patients presented evidence of depression, and this condition was significantly associated with p = 0).In total, 78 patients dropped out of treatment with cannabis during the first month for various reasons, mainly for the lack of pain reduction, side effects or both. The average pain reduction in drop-out patients was null or negative (∆VAS = −0.17) compared to the others (∆VAS = 1.7), and the difference was highly significant  between the drop-out patient group and those suffering from multiple adverse events, such as tachycardia, drowsiness, dry mouth and hyperactivity. Furthermore, there was a significant association (χ2 = 5.6 p < 0.018) between the drop-out phenomenon and the polymorphism (recessive model) of the gene CNR1 (CB1) rs1049353. The odds ratio for patients with the GG + GA genotypes vs. AA homozygotes was 2.4 (CL 1.1–5.2), indicating that the former were 2.4 times more likely to continue treatment with cannabis than AA homozygotes. Logistic regression confirmed the role of CNR1 polymorphism in the risk of treatment drop-out for AA homozygotes, excluding significant associations with all the other possible factors we tested.The χ2 test showed a strongly significant association , as group two was more strongly associated with anxiety and the use of medication (p = 0.0002). Those who took medication were at higher risk, probably because they were affected by more serious diseases.In respect to anxiety, the logistic analysis showed significant associations between the presence of anxiety and disease  not only showed no significant association, but remained very far from significance. It is very likely that the associations observed were in part disguised by the constant adjustment of cannabis dosages, being approximately doubled on average, but reduced in certain cases, and by the fact that approximately 30% of patients changed their type of cannabis during the first month of treatment to the “titrate” type.In this study, we showed that, despite the complexity of cannabis pharmacology and the difficulty in precisely quantifying the results of treatment with cannabis, it is possible to assess the role of certain genetic polymorphisms in patients and to explain part of the great inter-individual variability observed in pain reduction. On average, the pain reduction in remaining patients (non-drop-out) at the end of the first month amounted to approximately 20%, but with great variability. Part of this was significantly associated with three polymorphic candidate genes: C3435T, of the MDR1/ABCB1 gene, which encodes a transporter protein (MRP1), produces a “silent” missense variant, which, however, determines the reduction in the expression of the transporter protein [MDR1/ABCB1 gene in pain control, the pharmacological treatment aside.The rs1045642 polymorphism, also known as  protein . Patient protein . In this protein , confirm protein . An incr protein . It is i protein , suggestTRPV1 polymorphism (rs8065080), also known as c.1191A > G, is a common variant in the TRPV1 gene , which encodes, among others, vanilloid receptor subtype-1 and the capsaicin receptor. The polymorphism determined by rs8065080 was associated with salt sensitivity [The sitivity , the tolsitivity  and withsitivity . In our sitivity , as by msitivity . Cannabisitivity ,26.UGT2B7 gene encodes UDP-glucuronosyltransferase-2B7, involved in phase II metabolism, conjugating a variety of compounds such as analgesics (morphine), carboxylic non-steroidal anti-inflammatory drugs (ketoprofen) and anti-cancer drugs  [The ic acid) . The rs7ic acid)  and in tic acid) . In the ic acid) .CNR1 gene, rs1049353, was a therapy drop-out risk factor. This gene encodes the most relevant cannabinoid receptor, the polymorphism of which was extensively studied in depression therapy [The fact of having found three polymorphic genes which individually significantly influence pain decrease after treatment with cannabis poses the problem of the impact of their possible combinations in patients. As expected, patients simultaneously carrying the most favourable allelic combinations showed a greater pain reduction (∆VAS = 1.73) compared with those with a less favourable combination (∆VAS = 0.56). Considering genotype combinations, we could, therefore, group patients into good responders, intermediate responders and poor or non-responders. We are aware that this study included many variables, such as cannabis types, contents of active principles, different groups of diseases and patients’ overall clinical situations, the interactions of which were difficult to assess as they were not planned a priori, but could have important effects on the assessment of pain reduction. However, the results suggested that a patient’s genetic makeup is, at the moment, a significant descriptive factor of variability in the response to cannabis. Changes in cannabis dosages, doubled on average, which occurred during the first month and were empirically guided, were not associated with any factor, including genetic factors, thus, suggesting that the initial dosage, apparently low, was due to the caution of physicians who administered a drug which was not well known to patients who were treated for the first time. Furthermore, the association study showed that the A allele of the  therapy ,32.This study proved, for the first time, that certain polymorphic candidate genes may be associated with cannabis effects, both in terms of pain control and side effects, including therapy drop-out. This approach is, therefore, feasible and, if adequately developed, could possibly contribute to shedding light on the complex pharmacokinetics and pharmacodynamics of cannabis, making physicians more confident in its therapeutic use. We are aware that only by extensively expanding the polymorphic genes panel and the number of their polymorphisms could it be possible to hypothesize a more personalized therapy, aided by the knowledge of patients’ genetic characteristics. It is our opinion that an association study on the whole genome  could lead to important progress in this field.


IntroductionManagement of post-operative pain after cardiac surgery continues to be a challenge; inadequate management of pain can lead to increased morbidity, impaired physical function with potential delay in recovery, increased perioperative and chronic opioid consumption, increased cost of care, and a decreased quality of life. This study aimed to evaluate the effect of adding buprenorphine and magnesium to bupivacaine for superficial parasternal intercostal plane blocks (SPIB) on pain and opioid consumption in the first 24 hours after coronary artery bypass grafting (CABG).MethodsPatients undergoing CABG were divided into the following four groups: saline SPIB, SPIB with bupivacaine (BPVC), SPIB with bupivacaine and buprenorphine (BPVC+BPRN), and SPIB with bupivacaine, buprenorphine, and magnesium (BPVC+BPRN+MG). The primary outcomes were pain scores and opioid consumption after SPIB; the secondary outcomes were post-operative nausea and vomiting, time to extubation, and length of stay (LOS) in the intensive care unit and hospital.ResultsOne hundred thirty-four eligible patients undergoing CABG were randomized to either the saline (n=27), BPVC (n=20), BPVC+BPRN (n=24), or BPVC+BPRN+MG (n=29) group. All of the intervention groups combined  had decreased pain scores and decreased opioid consumption when compared to the saline group; although not statistically significant, visual analog scale (VAS) scores trended downward at most time points with BPVC versus saline, BPVC+BPRN versus BPVC, and BPVC+BPRN+MG versus BPVC+BPRN. There was no difference among the study groups in the incidence of post-operative nausea and/or vomiting (PONV), time to extubation, hospital LOS, and ICU LOS.ConclusionIn this prospective, double-blind, placebo-controlled trial, we found that SPIB with local anesthetic is effective at reducing VAS scores and opioid consumption after CABG. Further study is needed to determine whether the addition of adjuvants can further improve pain control and opioid consumption. Perioperative pain management continues to be a significant challenge in cardiac surgery after sternotomy. Inadequate postoperative analgesia results in increased morbidity, impaired physical function and delay in recovery, increased perioperative and chronic opioid consumption, increased cost of care, and a decreased quality of life . AdditioTraditionally, opioids have been the mainstay for perioperative pain management in patients undergoing cardiac surgery. However, a range of undesired effects including excessive sedation, respiratory depression, pulmonary aspiration, nausea, vomiting, constipation, urinary retention, pruritis, and ileus have led to the institution of multimodal analgesic regimens that include non-opioid analgesics and regional analgesic techniques in the perioperative period . NeuraxiCommonly used regional analgesic techniques for cardiac surgery to manage postoperative pain include pectoralis nerve blocks, serratus anterior plane blocks, erector spinae plane blocks, paravertebral blocks, transversus thoracic muscle plane blocks, and parasternal intercostal nerve blocks. These techniques have been shown to provide improved postoperative pain control and decrease opioid requirements while leading to fewer postoperative complications -13. SupeWhile current research suggests regional analgesic techniques are effective for pain reduction after cardiac surgery, the ideal formulation of local anesthetic and adjuvant medications necessary to provide an effective, and long-lasting block is still undefined. Bupivacaine is a local anesthetic that inhibits sodium channels that propagate action potentials in axons, dendrites, and muscles; additionally, bupivacaine inhibits N-methyl-D-aspartate (NMDA) receptor-mediated synaptic transmission in the spinal cord ,19. MagnThe primary objective of this study was to determine if the addition of buprenorphine and magnesium to bupivacaine for SPIB would reduce pain scores and opioid consumption in the first 24 hours after sternotomy for coronary artery bypass grafting (CABG). The secondary outcomes evaluated include the incidence of post-operative nausea and/or vomiting (PONV), time to extubation, and length of stay (LOS) in the intensive care unit (ICU) and in the hospital.According to our hypothesis, the addition of magnesium and buprenorphine to bupivacaine for SPIB would decrease pain scores and opioid consumption within the first 24 hours after CABG, decrease the incidence of PONV, decrease the time to extubation, and decrease the duration of both surgical intensive care unit (SICU) and hospital LOS, when compared to SPIB done with buprenorphine and bupivacaine, bupivacaine alone, and saline placebo.clinicaltrials.gov (NCT05003765). The investigators enrolled 134 consecutive patients undergoing isolated CABG with one of three cardiothoracic surgeons between August 2021 and June 2022. Written informed consent was obtained from each patient in the pre-operative holding area prior to surgery.This prospective, placebo-controlled, randomized, double-blind study was performed at St. Joseph Mercy Oakland Hospital in Pontiac, Michigan. Institutional review board approval was obtained from St. Joseph Mercy Oakland Hospital; the study was registered at ParticipantsPatients between 18 and 100 years of age were eligible. Men and women of all races and ethnic backgrounds undergoing isolated CABG under general anesthesia were enrolled.Patients were excluded based on the following criteria: patient refusal, emergency surgery, redo sternotomy, left ventricular ejection fraction <40%, preexisting pulmonary disease  or neurologic dysfunction, allergy to local anesthetics, significant hepatic or renal disease, unexpected additional valvular or aortic procedures during the scheduled CABG operations, chronic opioid use, and continued intubation for greater than 6 hours after surgery.Intraoperative managementAll participating patients received general endotracheal anesthesia with transesophageal echocardiography during their operations. Intraoperative opioid administration was left to the discretion of the cardiac anesthesiologist. SPIB  were performed by a single cardiothoracic surgery physician assistant with saline (control), 0.25% bupivacaine, 0.25% bupivacaine and 300 mcg buprenorphine, or 0.25% bupivacaine, 300 mcg buprenorphine, and 200 mg magnesium sulfate.Patients were randomly assigned to one of four groups using a computer-generated random number table. Participants, the cardiothoracic surgery team, the anesthesiology staff, and the nurses caring for the patients were blinded to group allocation. Patients in group 1  received SPIB using 40 mL of sterile saline. Below each rib (2-6) deep to the pectoralis major muscle and superficial to the intercostal muscles 4 mL of the solution was injected. Acceptable local anesthetic injection at each level was verified using direct visualization prior to sternal closure  over the ensuing 24 hours. Post-operative administration of opioids and other pain medications was determined by the critical care and cardiothoracic surgery teams. To facilitate comparison, total opioid consumption for all patients in this study was converted to oral morphine equivalents (OME). The following conversion equivalents were used: 5 mg morphine (PO)=5 mg hydrocodone (PO)=3.3 mg oxycodone (PO)=1.25 mg hydromorphone (PO)=0.25 mg hydromorphone (IV)=0.02 mg fentanyl (IV)=1.67 mg morphine (IV/IM/SC)=50 mg tramadol=50 mg meperidine (PO)=12.5 mg meperidine (IV/IM/SC)=33.33 mg codeine (PO)=20 mg codeine (IV/IM/SC) based on the recommendations of Statistical analysisThe primary outcomes of the investigation were total opioid consumption for (OME {mg}) 24 hours post-surgery and pain scores at time of extubation and 6, 12, 18, and 24 hours post-operation. Secondary outcomes included time from end of surgery to extubation, hospital LOS, ICU LOS, and incidence (percentage of the patients) of PONV requiring treatment during the first 24 hours following surgery. All outcomes were analyzed as continuous variables except for the incidence of PONV, which was treated as a categorical variable.2 tests, and Fisher exact tests, as appropriate. For the continuous data, the statistical differences between the four groups of the study, saline (n=27), BPVC (n=20), BPVC+BPRN (n=24), and BPVC+BPRN+MG (n=29), were determined using first by a one-way analysis of variance (ANOVA) and then by two-by-two comparison using the post-hoc Fischer Least Significant Difference (LSD) test. For the categorical data, the statistical difference was determined using Pearson χ2, followed by Yates continuity correction and the Fisher exact probability test. A p-value of less than 0.05 was considered to be statistically significant. A p-value of 0.05 <p <0.1 (significant one-tailed test) can indicate a trend that could become significant with stronger power in the study. Data are reported as number (percentage of patients) or mean±SEM (mean±standard error of mean) or mean±standard deviation (mean±SD). All the data were analyzed using SPSS version 24 .Demographic data were analyzed using t-tests, χFigure Table 2= 0.23, p=0.9726) and race   (mg) were compared between the saline (n=27) group and the three other block groups combined  (n=73). ANOVA analysis results were the following: pain score at extubation    and the incidence of PONV, that is, the percentage of the patients who experienced PONV within the first 24 hours after surgery  defines early extubation after cardiac surgery as within 6 hours; this time frame is an STS quality marker. However, the relationship between extubating patients within the 6-hour time frame and improved outcomes including decreased ICU LOS and hospital LOS is controversial; some have reported that this 6-hour extubation window is not rooted in physiologic evidence . It is mOur study is not without limitations. Our patient population consisted primarily of Caucasian males, even though all patients meeting inclusion criteria were consecutively enrolled during the study period. This limited demographic profile, although the groups were not statistically demographically different from each other, may limit the generalizability of the current study; an additional larger study may be required to confirm our findings. In addition, all SPIB were performed without ultrasound guidance, limiting the ability to confirm appropriate deposition of injectate into the correct plane. Instead, SPIB were performed by a single cardiothoracic surgery physician assistant under direct visualization using a landmark technique. We elected to perform SPIB without ultrasound to avoid potential sterility issues and to reduce the potential for postoperative sternal wound infection. Finally, given the relatively small study group, the study may not have been adequately powered to show statistical significance when comparing VAS scores between groups. Although the groups trended towards lower VAS scores as local anesthetic and additional adjuvant medications were added, larger group sizes may have revealed statistically significant differences.In summary, this is the first prospective, randomized, double-blind, placebo-controlled study investigating the use of bupivacaine plus multiple adjuvant medications in SPIB following cardiac surgery. Although we noted that VAS scores and post-operative opioid consumption were reduced in the intervention groups versus the placebo group, we were not able to definitively show that adding buprenorphine or buprenorphine and magnesium to bupivacaine provided better relief than bupivacaine alone; we did, however, see a trend toward lower pain scores in the groups with buprenorphine and buprenorphine and magnesium. We can definitively report that SPIB is effective at reducing VAS scores and opioid consumption after cardiac surgery (when compared to placebo), but further large-scale study to confirm the local anesthetic formulation that will have the greatest impact on pain control, opioid use, and reduction in side effects is indicated.Controlling perioperative pain after sternotomy for cardiac surgery continues to be a significant challenge to clinicians. SPIB is a simple and safe regional analgesic technique that has been shown to be effective in patients having sternal pain after cardiac surgery.In this prospective, double-blind, placebo-controlled trial, we found that SPIB was effective at reducing pain scores and opioid consumption when compared to placebo. We also saw a trend toward lower pain scores in intervention groups with buprenorphine and buprenorphine and magnesium included in the SPIB. Further large-scale study is needed to confirm whether the addition of these adjuvant medications to local anesthetic in SPIB can significantly enhance pain relief, reduce opioid consumption, and decrease side effects.


Moyamoya syndrome in a sickle cell disease patient may be a difficult task to manage in the setting of a vaso-occlusive pain crisis. Maintaining stable blood pressure is necessary to prevent stroke as both hypertension and hypotension can be detrimental to the patient, leading to hemorrhagic and ischemic stroke, respectively. Opioid management for pain control in such patients must be taken into consideration. Because every patient is unique, opioid regimens should be optimized to relieve patients’ specific pain while also practicing non-maleficence in preventing hypotension and strokes. Moyamoya is a Japanese term translated as “puff of smoke” which is used to describe the pattern of neovascularization of tiny blood vessels in the brain compensating for blocked internal carotid arteries. Moyamoya disease (MMD) is defined by this radiographic finding, while moyamoya syndrome (MMS) is the presence of MMD in addition to other comorbidities such as sickle cell disease, Down’s syndrome, or neurofibromatosis . MMD typThroughout North America, little data are available on MMS associated with sickle cell disease. MMS is exceedingly rare with an estimated incidence of 0.086 per 100,000 persons in the western demographic of the United States, specifically in Washington and California . Over a A 50-year-old female with a medical history of sickle cell disease, seropositive rheumatoid arthritis, and MMS complicated by multiple strokes with residual right-sided weakness, cognitive impairment, and seizures presented to our emergency department with severe pain in her chest, lower back, and bilateral legs, more intense than her typical acute vaso-occlusive pain episodes. The patient’s mother reported that home doses of combination oxycodone and acetaminophen did not relieve her pain. Initial vitals were notable for a temperature of 36.4°C, blood pressure of 92/44 mmHg, pulse of 98 beats per minute, and oxygen saturation in the 70s. Labs were significant for hemoglobin of 3.3 g/dL (baseline 5 g/dL), lactate dehydrogenase 667 U/L, and reticulocyte 15%. On further evaluation and workup, the patient was also found to have a urinary tract infection (UTI). She was then admitted to our general medicine floor for management of her vaso-occlusive crisis secondary to UTI.According to the patient’s mother, her primary caregiver, she was diagnosed with sickle cell disease at age three. She had her first stroke at eight years of age, was diagnosed with MMS at ten years, and subsequently had multiple strokes. The patient’s home pain regimen included oxycodone/acetaminophen 5-325 mg taken as needed for pain. Other home medications included aspirin, hydroxychloroquine, levetiracetam, and topiramate.During the hospital course, the patient was initially started on hydromorphone 0.5 mg intravenously every four hours as needed for pain. Given the patient was opiate-naïve, she developed multiple episodes of hypotension and bradycardia with systolic blood pressure (SBP) of 54-105 mmHg, diastolic blood pressure (DBP) of 34-74 mmHg, and heart rate of 48-98 beats per minute. To avoid further hypotension, bradycardia, and respiratory depression, hydromorphone was discontinued, and the pain regimen was adjusted to oxycodone-acetaminophen 5-325 mg every six hours. Vitals returned to the baseline range after adjustment of medication, SBP ranged between 107 and 118 mmHg, DBP ranged between 61 and 71 mmHg, heart rate ranged between 61 and 71 bpm, and the pain was controlled. Other considerations included avoiding lidocaine transdermal patches because even minimal lidocaine absorption into the circulation could be hemodynamically detrimental in the patient. Baclofen was also added to address musculoskeletal pain.In addition to pain management, the patient was given gentle intravenous fluid hydration and a total of three units of packed red blood cells with improvement of blood pressure and hemoglobin levels to 6.6 g/dL at baseline on discharge. Her UTI was also treated with antibiotics. The patient remained hemodynamically stable on the adjusted pain regimen without signs of acute stroke throughout her hospital course. Computed tomography scans of the head without contrast are shown in Figures In patients with sickle cell disease, MMS can be seen in about 20-30% of cases and can be detected using brain angiograms . MoyamoyRegarding antiplatelet therapy, studies on the benefit of antiplatelet agents in MMD are limited; however, antiplatelet therapy with aspirin or cilostazol is commonly incorporated into practice. In a study using the Korean National Health Insurance database, antiplatelet therapy was found to reduce mortality in patients with MMD compared to those who did not use antiplatelet therapy. In particular, cilostazol provided more survival benefit compared to aspirin, clopidogrel, and other antiplatelet agents .To prevent subsequent strokes, surgical revascularization can also be considered in some cases. In a study monitoring the features and outcomes of MMD in North America, after the initial symptoms of MMD, mostly ischemic stroke, the rate of recurrent strokes was decreased by 17% in those who underwent moyamoya revascularization compared to 65% in those who did not [The complications of moyamoya angiopathy, such as seizures and chronic headaches, should also be clinically managed with antiepileptics and analgesics . ConcernOther analgesics can be considered such as tapentadol and morphine. In a study involving 1,464 patients over 15 weeks that evaluated blood pressure and heart rate changes between oxycodone and tapentadol, oxycodone was found to have a more significant effect in decreasing systolic and diastolic blood pressure from patients’ baseline. The study concluded that the management of pain is safer using tapentadol in patients with chronic pain and hypertension . In addiMMD is an extremely rare disease, especially in North America and non-Asian populations. In the management of vaso-occlusive pain with opioids in patients with sickle cell disease and MMS, careful consideration should be taken to monitor blood pressure. Hypotension should be avoided to prevent decreased brain perfusion, especially in patients with MMS who are at increased risk of stroke. In the event of continuous hypotension due to oxycodone, patients can be switched to tapentadol if the pain is responsive. Other long-term and definitive management can be performed such as revascularization surgery to reduce subsequent strokes.


Background: The aim of our observational study is to compare the therapeutic efficacy of combined treatment of oxygen–ozone therapy and oral treatment with alpha-lipoic acid (ALA) + palmitoylethanolamide (PEA) and myrrh in patients with peripheral neuropathic pain (sciatica) on radicular disc conflict from disc herniation and the results obtained with oxygen–ozone treatment alone. Methods: We enrolled 318 patients with the neuroradiological diagnosis of disc herniation performed with computed tomography (CT) or magnetic resonance imaging (MRI) and symptoms characterized by low back pain complicated by sciatica, which we divided into two groups. Group A was composed of 165 patients who were treated only with oxygen–ozone therapy with CT-guided intraforaminal technique, while the remaining 153 (Group B) have undergone combined oral treatment with ALA + PEA and myrrh. Follow-up visits for the evaluation of the clinical outcome of the treatment were conducted after 60 ± 8 days using a modified version of McNab’s method. Results: At the clinical check-up, 126/165 patients included in Group A had a complete remission of pain (76.4%), while in Group B, 119/153 (77.8%) had a complete remission of pain. Conclusion: The results highlight how the treatment associated with ozone therapy and oral administration of alpha-lipoic acid + palmitoylethanolamide and myrrh is preferred over the simple treatment with only ozone in such patients in the phase of greatest acuity of the disease, where the pain appears to be better controlled. Oxygen–ozone therapy for the treatment of herniated discs was introduced in 1985. Over the years, numerous clinical cases have been presented in the literature that has reported positive results ranging from 75% up to almost 90% in the treatment of low back pain, complicated or not by sciatica from disc-radicular impingement, determined by the presence of a herniated intervertebral disc ,21,22.Low back pain and lumbosciatica are highly disabling pathologies, more and more widespread in every social category, which are manifesting themselves at an increasingly precocious age. They arise acutely, following unusual efforts or movements, or slowly, often with progressive aggravation.Lumbago and sciatica are painful conditions that are estimated to affect 5 in every 10,000 Western adults. They can be supported by numerous vertebral pathologies, often concomitant: diseases of the disc, of the facet joints, spondylolysis (with or without listesis), somatic and interapophyseal arthrosis, stenosis of the vertebral canal, radicular and synovial cysts, meningiomas, primary or metastatic neoplastic pathology, etc. ,23.To choose the best therapy, in cases of low back pain and/or sciatica pain, a precise diagnosis conducted after a careful objective examination and supported by suitable instrumental examinations is therefore essential. In addition to standard radiograms of the spine, in these patients, computed tomography (CT) and/or magnetic resonance imaging (MRI) are therefore of primary importance.In our study, we exclusively recruited patients with low back pain complicated or not by sciatica pain as by disc-radicular impingement from soft disc hernia .Among the many causes of low back/lumbosciatalgia, the herniated intervertebral disc is the most common cause of sciatica, affecting 95% of patients with this disorder. The protruding annular fibers of the disc can compress the radicular nerve, causing pain. Oxidative stress potentiates peripheral neuropathy of the lower limbs, reducing neuronal function and local blood flow, resulting in a decrease in the supply of nutrients to the supporting cells.Considering as a first therapeutic approach, the targeted treatment with oxygen–ozone with intraforaminal CT-guided technique , exploit® myrrh is a dry extract of Commiphora myrrha gum resins with a high content of bioactive furanodienes, obtained through a patented extraction process, which allows preserving all the properties of the original raw material. PEA is, on the other hand, a natural compound rich in fatty acids, which, in the body, acts as a biological modulator, favoring the physiological tissue response [MyrLiqresponse ,37,38,39ALA/PEA/Myhrr is also effective in the management of complex regional pain syndrome, and as anti-inflammatory, it has been hypothesized that ALA/PEA/M could act on cytokine storm in COVID-19 patients ,41.®) is required.In particular, the use of fast–slow tablets represent a food supplement that supports the normal function of the nervous system. They are also useful in cases of lumbosciatica, carpal or tarsal tunnel syndrome, peripheral neuropathies, alcoholic neuropathies, diabetic neuropathies, and in all those cases in which supplementation of alpha-lipoic acid (thyoptic acid), PEA, and myrrh , oxygen–ozone treatment was combined with 800 mg/day of ALA + 600 mg/day of PEA + 200 mg/day of myrrh orally.We treated a total of 171 males (88 in group A and 83 in group B) and 147 females (79 in group A and 68 in group B) aged between 24 and 66 years (median age: 47.2) with low back pain and/or sciatica. In our study, we exclusively recruited patients with pain as by disc-radicular impingement from soft disc hernia . Written informed consent was obtained from the patients to publish this paper.On enrollment, the name, date of birth, date of enrollment, date of treatment, and clinical details were recorded for each patient listing the type of pain, irradiation, paranesthesia, Lasègue’s sign, degree of sensitivity, lower limb reflexes, plantar extension of the foot, and dorsal extension of the big toe. Before enrollment, all patients were subjected to CT or MRI scans.Patients had acute or chronic low back pain and sciatica, which was unilateral or irradiating along with the innervation territories of L3 (19 patients), L4 (159 patients), L5 (105 patients), and S1 (35 patients). Patients with bilateral lower back and sciatic nerve pain and those with electromyographic features of neurogenic injury and/or denervation were excluded.The injection site was disinfected, and local anesthesia was applied using an ethyl chloride spray in all patients. Infiltrations were done by specialist neuroradiologists at the Neuroradiology Service of Istituto Clinico Città di Brescia (Brescia), Cardarelli Hospital Naples, and Casa di Cura Brebbia (Varese).The puncture site was identified by CT scan and marked on the patient’s skin. The distance from this point to the foramen was subsequently measured.A 22 G Terumo needle  was positioned 2–3 mm from the foraminal region, close to the ganglion of the affected nerve root a. A CT s2-O3 was infiltrated by injecting 3 ml of the gas mixture at 25 µg/mL close to the neural foramen, then retracting the needle a few millimeters and injecting another 5 ml of the mixture to involve the facet joint region. CT scans were then used to check the correct distribution of the gas mixture in the foramen and facet joint  with constant pressure during ozone intake operation. There was total non-toxicity, as the titanium, Teflon, glass, and silicon, which are inert to ozone, were in contact with the gas . All patients included in the study underwent three treatments with oxygen–ozone therapy over 30 days with distance of 9 ± 2 days between the first and second therapeutic session and 18 ± 2 between the second and third.In the 153 patients who were combined with oral administration of 800 mg/day of ALA + 600 mg/day of PEA + 200 mg of myrrh, patients took 2 tablets/day on an empty stomach 30 minutes before breakfast and before dinner (morning and evening). The two assumptions were separated by about ten hours for 20 days of total therapy.The content of each single tablet provides 800 mg of alpha-lipoic acid, 600 mg of PEA, and 200 mg of myrrh e.s. Patients underwent clinical evaluation after 9 ± 2 days from the first treatment, after 18 ± 2 days from the second treatment, and at the end of the study expected 60 ± 8 days from the start of therapy.Excellent: resolution of pain and return to normal activity carried out prior to pain onset.Good or satisfactory: more than 50% reduction of pain.Poor: partial reduction of pain below 70%.Moreover, the clinical outcome was assessed in all patients; follow-up visits occurred using a modified version of McNab’s method ,43:Excel2-O3 + ALA (ALA) and the O2-O3 (CTR) groups, we used an ordinal logistic regression model . Such model employed the outcome  as response variable and treatment , occasion , and a treatment X occasion  interaction as predictors. The model employed cluster confidence intervals to consider repeated measures. Using this model, the difference in the proportion of patients with a poor, good, and excellent outcome between the ALA and CTR groups on the different occasions was calculated using a within-time between-group contrast with Bonferroni correction for 9 groups (1 difference X 3 outcome levels X 3 occasions). Statistical analysis was performed using Stata 17.0 .To quantify the time-related change in the proportion of subjects with a poor, good and excellent outcome between the OThe results of the statistical analysis are reported in At the clinical check-up conducted 60 days ± 8 from the end of the treatment using a modified version of McNab’s method, 116/165 patients in Group A had a complete remission of pain (70.3%) while 21 (12.7%) and 28 (17.0%) had no benefit from the treatment, reporting a partial remission of painful symptoms, while in Group B 119/153 (77.8%) had a complete remission of pain, 13 (8.5%) considered the outcome of the treatment sufficient and 21 (13.7%) insufficient. The patients were also clinically evaluated after the first guided CT infiltration with oxygen–ozone at 9 ± 2 days, and in the patients of Group A, 83/165 (50.3%) reported an excellent result after the treatment, while 37 (22.4%) patients reported a satisfactory and 45 (27.3%) poor clinical result; in Group B, 92/153 patients (60.1%) reported an excellent clinical result, 28 (18.3%) relatively good, and 33 (21.6%) insufficient. In the subsequent intermediate check-up 18 ± 2 days after the second oxygen–ozone therapy session, 94/165 patients in Group A reported an excellent result (57%), while 32 (19.4%) were relatively satisfied, and 39 (23.6%) did not report any improvement; in Group B, the patients who reported an excellent/good clinical result were 106/153 equal to 69.3% .2-O3 + ALA as compared to O2-O3 was associated with a higher number of excellent results on occasion II , occasion III , and 60 days . These promising data suggest the utility of performing a randomized controlled trial to ultimately ascertain the efficacy of ALA as an adjunct to O2-O3 therapy for the treatment of sciatic pain due to herniated disks.In this observational study, we found that treatment with OIn recent years, several studies have demonstrated the utility of oxygen–ozone therapy in the treatment of herniated discs ,20,21,22We believe, in this regard, that the administration of intraforaminal ozone CT-guided mode with the associated proposal guarantees control of the needle tract ,4,5,6.The possibility of curative oxygen–ozone is, in this regard, high because of the improvement of local circulation with eutrophication in the proximity of the nerve root, compressed and suffering both muscle spasms. It can normalize the level of cytokines and prostaglandins with anti-inflammatory and pain relievers. It increases the production of superoxide dismutase (SOD) with the minimization of oxidizing reagents (reactive oxygen species) ,19,24,25The rapid resolution of pain with no complications, the ease of performing the method and complete control of infiltration by CT allow today to propose intraforaminal CT-guided oxygen–ozone therapy technique as a viable alternative to surgical treatment of disc herniation if the latter is not considered essential and therefore a method of choice between conservative therapies.According to the results shown in our sample of 318 patients, both in the intermediate checks at 9 ± 2 days from the first treatment and at 18 ± 2 days from the second treatment, the therapeutic results differ slightly with regard to the patients included in Group A and Group B. However, it is possible to see how in the patients included in Group B corresponding to the combined treatment, positive results are assessed slightly more, and certainly, this result can be traced back to the combined action of ALA + PEA + myrrh, which consists of further and effectively relieving the neuropathic symptoms.Therefore, based on the results, we conclude that the association of a minimally invasive therapy such as oxygen–ozone therapy under CT scan with intraforaminal technique and the oral administration of 800 mg/day of ALA + 600 mg/day of PEA + 200 mg of myrrh to subjects afflicted by low back pain complicated by sciatica can be considered an excellent therapeutic solution, improving the good final clinical result with better control of symptoms, particularly in the first phase of the disease, with the final aim of offering a valid conservative alternative to a possible surgical solution. However, we believe that the present study should be extended to an even larger sample of patients.


Is tuina combined with yijinjing more effective than tuina alone for nonspecific chronic neck pain?In this randomized clinical trial of 102 individuals with nonspecific chronic neck pain, the combined therapy had a statistically significant advantage in reducing pain at week 8 compared with tuina therapy alone. The effectiveness was still present at 12-week follow-up.These findings suggest that a combination of tuina therapy and yijinjing exercise was more effective than tuina therapy alone in the treatment of patients with nonspecific chronic neck pain. This randomized clinical trial compares tuina therapy combined with yijinjing exercise with tuina therapy alone for the treatment of patients with nonspecific chronic neck pain. Both tuina therapy and yijinjing exercise were beneficial to patients with nonspecific chronic neck pain, but the evidence for this combination is limited.To investigate the effectiveness of tuina therapy combined with yijinjing exercise compared with tuina therapy alone for patients with nonspecific chronic neck pain.A 12-week, open-label, analyst-blinded randomized clinical trial  was conducted from September 7, 2020, to October 25, 2021. A total of 102 participants with nonspecific chronic neck pain were recruited, and data were analyzed from December 10, 2021, to March 26, 2022.Participants in the tuina group or tuina combined with yijinjing group received 3 sessions of tuina therapy per week for 8 weeks, for a total of 24 sessions. Participants in the tuina combined with yijinjing group practiced yijinjing 3 times a week for 8 weeks, including an instructor-guided exercise at the hospital and 2 self-practice exercises at home.The primary outcome was change in visual analog scale (VAS) score from baseline to week 8. Secondary outcomes included Neck Disability Index scores, Self-rating Anxiety Scale scores, tissue hardness, and active range of motion.P < .001) between the tuina group and the tuina combined with yijinjing group. The effectiveness of tuina combined with yijinjing in treating nonspecific chronic neck pain remained at the 12-week follow-up.This randomized clinical trial recruited 102 patients  who were randomized to 2 groups. All 102 patients (100%) completed all the outcome measurements. The mean difference in VAS scores from baseline at week 8 for the tuina combined with yijinjing group was −5.4 . At week 8, the difference in VAS score was −1.2 (95% CI, −1.6 to −0.8; In this randomized clinical trial, for patients with nonspecific chronic neck pain, tuina combined with yijinjing was more effective than tuina therapy alone in terms of pain, functional recovery, and anxiety at week 8, and effectiveness remained at week 12. A combination of tuina and yijinjing should be considered in the management of nonspecific chronic neck pain.ChiCTR2000036805Chinese Clinical Trial Registry:  Patients with symptoms that persist for more than 3 months can be diagnosed as having nonspecific chronic neck pain (NCNP).3 In addition, NCNP is often associated with anatomical, psychological, social, and occupational factors. Anxiety and depression are also thought to be associated with higher levels of pain in patients with musculoskeletal pain.4Neck pain is a common musculoskeletal disorder with a high prevalence worldwide. It is the fourth most common cause of disability in the US. The mean lifetime prevalence of neck pain is 48.5% , the third highest in the US after diabetes and heart disease.6 Therefore, nondrug therapy has attracted more attention.7 Exercise is considered a treatment modality for pain relief. A previous systematic review found that multiple forms of exercise are beneficial to neck pain and disability.8 Complementary and alternative medicine, such as manual therapy, osteopathic therapy, and Qigong, have been used widely in treating NCNP.10Because NCNP often occurs without any established pathologic process and cause, it is difficult to adopt precise treatment methods. Therefore, drugs, intra-articular injections, and surgery are often used as common treatments. However, the efficacy of these treatments is not guaranteed.11 Systematic reviews have reported that tuina therapy can alleviate pain and relax stiff soft tissue for patients with NCNP.13 However, research on the direct physiologic mechanisms of tuina therapy for neck pain is relatively limited. Two previous basic studies on animal experiments showed that pain behavior of mice was improved after simulating massage manipulation, which was associated with reduced peripheral inflammation mediated by the mechanosensitive channel protein Piezo and senescence-related pathways.15 A recent study simulated the treatment process of tuina manipulation and found that the analgesic effect on a neuropathic pain model may be related to the inflammatory pathway regulated by noncoding RNA.16 Yijinjing is a type of traditional Chinese exercise that puts emphasis on the coordination of posture, meditation, and breathing. It is a moderately intense mind-body exercise that is easy to practice with few limitations.17 The results of a systematic study showed that physical and mental exercises, including yijinjing, are beneficial for the recovery of neck pain and disability.18 Two recent studies on the neuroimaging of patients with stroke after a yijinjing intervention reported that it can modulate brain neural network connections, which may be a central mechanism of its analgesia.19Tuina is a Chinese manual therapy that consists of 2 passive treatments. One is soft tissue manipulation, which consists of manual techniques, such as pressing, pushing, and kneading. The other is spinal manipulation, including high-velocity, low-amplitude thrust procedures or low-velocity, variable-amplitude mobilization.20 Thus, a 12-week, open-label, analyst-blinded randomized clinical trial was conducted to assess the effectiveness of tuina combined with yijinjing in treating NCNP. The results were measured by the patient-reported outcome visual analog scale (VAS) scores after the 8-week intervention. We hypothesized that tuina combined with yijinjing would play a better role in improving pain, disability, and anxiety.Although tuina and yijinjing have been widely used in clinical treatment of NCNP in China, few high-level randomized clinical trials have been performed because of the limitations of traditional Chinese medicine research methods. In addition, nondrug therapy integrated into pain management is recommended by a clinical practice guideline.21 A single-center, open-label, assessor-blinded randomized clinical trial was performed from September 7, 2020, to November 23, 2021, at Yueyang Hospital of Integrated Traditional Chinese and Western Medicine affiliated with Shanghai University of Traditional Chinese Medicine. All participants were recruited mainly through online social platforms, advertisements, and hospital posters. All participants provided written informed consent. The study was performed in accordance with the principles of the Declaration of Helsinki22 and approved by the Regional Ethics Review Committee of Yueyang Hospital. The reporting of the study complies with the Consolidated Standards of Reporting Trials (CONSORT) reporting guideline. The trial protocol can be found in Full details of the trial have been published.Participants with confirmed NCNP were eligible for the present study. Inclusion criteria were as follows: men or women aged 20 to 50 years whose VAS scores were 3 or higher and Neck Disability Index scores were 10 or higher, with chronic neck pain persisting for at least 3 months, with no history of shoulder and neck surgery, and with negative results on the neck distraction test, Spurling neck compression test, and Adson test. Exclusion criteria were as follows: specific disorders of the cervical spine, such as cervical radiculopathy or myelopathy; history of whiplash injury and/or head or neck injuries; being pregnant or lactating; neck pain radiating into the upper limb; history of severe trauma or tumor; having received clinical treatment for neck pain in the past 3 months; being unable to speak or write Chinese; adverse reactions to tuina and yijinjing; undergoing tuina or yijinjing in the past 3 months; and poor cooperation.After recruitment and baseline measurements, an independent office employee at the department generated the randomization list by a random-number generator . The randomization database was prepared at the same time. The random numbers were placed in sealed envelopes that had been numbered in order. The therapist opened envelopes sequentially in front of the patients and allocated the patients to the 2 groups in a 1:1 ratio randomly.Except for the tuina therapist and yijinjing teacher, other researchers, including statisticians, outcome assessors, and data analysts, were blinded to group assignments. The tuina therapist and yijinjing teacher were not involved in the outcome assessment or data analysis.Patients in both the tuina group and the tuina combined with yijinjing group received a total of 24 tuina treatment sessions (3 sessions per week for 8 consecutive weeks). Tuina was performed by a senior therapist who held a Traditional Chinese Medicine Practitioner Qualification License for more than 10 years. The intensity level of tuina was based on a physical examination and the therapist’s clinical experience after careful communication with each participant. A 3-step protocol, including soft tissue manipulation, clicking acupoint manipulation, and spinal manipulation, was performed by the tuina therapist to alleviate neck pain and restore neck function by relaxing the soft tissue of the neck and shoulder  was assessed with an electronic spine measuring device. Normal AROM of the neck was 30° to 45° flexion and extension, 30° to 45° left and right lateral flexion, and 60° to 80° left and right rotation. The measuring method is shown in eAppendix 1 in The primary outcome was the change in VAS score at the end of the intervention (week 8).These outcomes were measured by blinded researchers. To avoid disclosing group assignments during the trial, patients were allowed only minimal conversation beyond what was necessary to measure the results at each measurement point. The researchers who used the digital algometer and the electronic spine measuring device participated in the 1-week training to understand how to use the instruments and passed relevant tests before participating in the trial. They were taught how to communicate with patients to avoid unnecessary conversation during the evaluation. We also collected outcome data at 12 weeks as an exploratory end point.27 which showed that the mean (SD) VAS scores were 5.5 (1.1) in the tuina group and 4.7 (1.3) in the tuina combined with yijinjing group after an 8-week intervention. Under the assumption that the superior effect was 1.3 of the difference in VAS score, with α = .05 and β = 0.1, the sample size was determined to be 84 patients (42 per group). With an assumed 20% dropout rate, 102 patients were recruited into this trial.The sample size calculation was based on a previous study (n = 78) performed in 2016,P < .05. For the primary outcome, VAS scores were assessed by using the linear mixed-effects model with the interaction effects of time and group. Participants who did not complete the study were treated as having no change from baseline at all times. A Bonferroni correction was used to account for multiple comparisons. Correlation analysis was conducted between the difference of the tissue hardness and the other outcome measures by the Pearson correlation analysis. All statistical analyses were conducted with SPSS software, version 24.0 (SPSS Inc).Data were analyzed from December 10 to March 26, 2022. Data analysis was based on the intention-to-treat principle. Descriptive analysis was used for the baseline characteristics of the patients in each group. All numerical data are presented as mean (SD). For quantitative data that did not conform to a normal distribution, data are expressed as median (IQR). In all analyses, statistical significance was accepted as a 2-tailed Of 202 potential participants who were screened, 102 patients (50.4%) with NCNP  who met the inclusion criteria were randomized to the tuina group (n = 51) or the tuina combined with yijinjing group (n = 51) . All 102P < .001) compared with the tuina group after the 8-week intervention period. A comparison of the VAS scores in the 2 groups is shown in –3.7 [–4.7 to –2.8] for right upper trapezius muscle; and active range of motion, 3.8°  for flexion, 4.2°  for extension, 3.8°  for left lateral flexion, 3.5°  for right lateral flexion, 6.6°  for left rotation, and 4.4° ) for right rotation.The secondary outcomes are given in At the 12-week follow-up, the tuina combined with yijinjing group continued to show superior effectiveness for the treatment of NCNP . There were significant within-group differences in outcomes at weeks 4, 8, and 12. No adverse events occurred throughout the trial.r = −0.378; P = .006) and right rotation . The difference in the tissue hardness of left upper trapezius muscle was positively correlated with the difference in the tissue hardness of right upper trapezius muscle . The difference in the tissue hardness of the right upper trapezius muscle was negatively correlated with the difference in flexion  and right rotation . All outcomes are shown in eAppendix 3 in Correlation analysis was conducted for the difference of the tissue hardness of the left and right upper trapezius muscle and the difference of scales and AROM before (week 0) and after intervention (week 8) in the tuina combined with yijinjing group. The difference in the tissue hardness of the left upper trapezius muscle was negatively correlated with the difference in flexion . This design is to capture the maximum possible treatment effect, assuming that most benefit occurred immediately after the intervention and 12-week follow-up. Longer-term results are more clinically meaningful and should be collected and analyzed in future studies. Seventh, no control group was used because tuina therapy is considered experimental, and whether yijinjing exercise alone has a good effect on NCNP needs to be verified in future studies.In this randomized clinical trial, patients with NCNP who received tuina combined with yijinjing showed greater improvement in terms of pain intensity, disability, and anxiety than those who underwent tuina therapy. Tuina combined with yijinjing can be recommended for routine use as supplemental therapy for pain control in patients with NCNP.