Two-year efficacy and safety of relugolix combination therapy in women with endometriosis-associated pain: SPIRIT open-label extension study.

STUDY QUESTION: What is the efficacy and safety of long-term treatment (up to 2 years) with relugolix combination therapy (CT) in women with moderate to severe endometriosis-associated pain? SUMMARY ANSWER: For up to 2 years, treatment with relugolix CT improved menstrual and non-menstrual pain, dyspareunia, and function in women with endometriosis; after an initial decline of <1%, the mean bone mineral density (BMD) remained stable with continued treatment. WHAT IS KNOWN ALREADY: Endometriosis is a chronic condition characterized by symptoms of dysmenorrhea, non-menstrual pelvic pain (NMPP), and dyspareunia, which have a substantial impact on the lives of affected women, their partners, and families. SPIRIT 1 and 2 were phase 3, randomized, double-blind, placebo-controlled studies of once-daily relugolix CT (relugolix 40 mg, oestradiol 1 mg, norethisterone acetate 0.5 mg) in premenopausal women (age 18-50 years) with endometriosis and moderate-to-severe dysmenorrhea and NMPP. These trials demonstrated a significant improvement of dysmenorrhea, NMPP, and dyspareunia in women treated with relugolix CT, with minimal decline (<1%) in BMD versus placebo at 24 weeks. STUDY DESIGN, SIZE, DURATION: Patients participating in this open-label, single-arm, long-term extension (LTE) study of the 24-week SPIRIT pivotal studies (SPIRIT 1 and 2) received up to an additional 80 weeks of once-daily oral relugolix CT treatment between May 2018 and January 2023. PARTICIPANTS/MATERIALS, SETTING, METHODS: Premenopausal women with confirmed endometriosis and moderate to severe dysmenorrhea and NMPP who completed the 24-week pivotal studies (SPIRIT 1 and 2 trials; Giudice et al., 2022) and who met all entry criteria were eligible to enrol. Two-year results were analysed by treatment group based on original randomization in pivotal studies: relugolix CT, delayed relugolix CT (relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT), or placebo→relugolix CT (placebo for 24 weeks followed by relugolix CT). The primary endpoints of the LTE study were the proportion of dysmenorrhea and NMPP responders at Week 52 and Week 104/end-of-treatment (EOT). A responder was a participant who achieved a predefined, clinically meaningful reduction from baseline in Numerical Rating Scale (NRS) scores (0 = no pain, 10 = worst pain imaginable) for the specific pain type with no increase in analgesic use. The predefined clinically meaningful threshold for dysmenorrhea was 2.8 points and for NMPP was 2.1 points. Secondary efficacy endpoints included change from baseline in Endometriosis Health Profile-30 (EHP-30) pain domain scores, a measure of the effects of endometriosis-associated pain on daily activities (function), NRS scores for dysmenorrhea, NMPP, dyspareunia, and overall pelvic pain, and analgesic/opioid use. Safety endpoints included adverse events and changes in BMD. MAIN RESULTS AND THE ROLE OF CHANCE: Of 1261 randomized patients, 1044 completed the pivotal studies, 802 enrolled in the LTE, 681 completed 52 weeks of treatment, and 501 completed 104 weeks of treatment. Demographics and baseline characteristics of the extension population were consistent with those of the original randomized population. Among patients randomized to relugolix CT at pivotal study baseline who continued in the LTE (N = 277), sustained improvements in endometriosis-associated pain were demonstrated through 104 weeks. The proportion of responders at Week 104/EOT for dysmenorrhea and NMPP was 84.8% and 75.8%, respectively. Decreases in dyspareunia and improvement in function assessed by EHP-30 pain domain were also sustained over 2 years. At Week 104/EOT, 91% of patients were opioid-free and 75% of patients were analgesic-free. Relugolix CT over 104 weeks was well tolerated with a safety profile consistent with that observed over the first 24 weeks. After initial least squares mean BMD loss <1% at Week 24, BMD plateaued at Week 36 and was sustained for the duration of 104 weeks of treatment. Efficacy and safety results were generally consistent in women in the placebo→relugolix CT and delayed relugolix CT groups. LIMITATIONS, REASONS FOR CAUTION: The study was conducted as an open-label study without a control group over the 80 weeks of the extension period. Of the 802 patients who were enrolled in this LTE study, 681 patients (84.9%) and 501 patients (62.5%) of patients completed 52 and 104 weeks of treatment, respectively. In addition, there currently are no comparative data to other hormonal medications. Finally, a third (37.4%) of the study population terminated participation early. WIDER IMPLICATIONS OF THE FINDINGS: In conclusion, relugolix CT offers an additional option to help address an important unmet clinical need for effective, safe, and well-tolerated medical treatments for endometriosis that can be used longer-term, reducing the need for opioids and improving quality of life. The findings from this study may help support the care of women with endometriosis seeking longer-term effective medical management of their symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by Myovant Sciences GmbH (now Sumitomo Pharma Switzerland GmbH). C.M.B. reports fees from Myovant, grants from Bayer Healthcare, fees from ObsEva, and Chair of ESHRE Endometriosis Guideline Group (all funds went to the University of Oxford); N.P.J. reports personal fees from Myovant Sciences, during the conduct of the study, personal fees from Guerbet, personal fees from Organon, personal fees from Roche Diagnostics; S.A.-S. reports personal fees from Myovant Sciences, personal fees from Bayer, personal fees from Abbvie, personal fees from UpToDate; J.S.P., and R.B.W. are employees and shareholders of Myovant Sciences; J.C.A.F. and S.J.I. are shareholders of Myovant Sciences (but at time of publicaion are no longer employess of Myovant Sciences); M.S.A. and K.W. have no conflicts to declare; V.M. is a consultant to Myovant; L.C.G. reports personal fees from Myovant Sciences, Inc and Bayer. The authors did not receive compensation for manuscript writing, review, and revision. TRIAL REGISTRATION NUMBER: NCT03654274.

Opium tincture has anti-propulsive effects in patients with chronic diarrhea: a randomized, placebo-controlled, and cross-over trial.

OBJECTIVE: Chronic diarrhea affects approximately 5% of the population. Opioids inhibit gastrointestinal motility, and opium tincture has shown anti-propulsive effects in healthy, but no controlled studies of its clinical efficacy exist. We aimed to investigate the anti-propulsive and central nervous system (CNS) effects of opium tincture in patients with chronic diarrhea. MATERIALS AND METHODS: The study was a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea refractory to standard treatment. Participants received opium tincture or placebo during two intervention periods, each lasting seven days. Bowel movements were recorded daily, and gastrointestinal transit time was investigated with the wireless motility capsule system. Gastrointestinal symptoms, health-related quality of life, and CNS effects (pupil size, reaction time, memory, and general cognition) were also investigated, along with signs of addiction. RESULTS: Eleven subjects (mean age: 45 ± 17 years, 46% males) with a median of 4.7 daily bowel movements were included. The number of daily bowel movements was reduced during opium tincture treatment to 2.3 (p = 0.045), but not placebo (3.0, p = 0.09). Opium tincture prolonged the colonic transit time compared to placebo (17 h vs. 12 h, p < 0.001). In both treatment arms, there were no changes in self-reported gastrointestinal symptoms, health-related quality of life, or CNS effects, and no indication of addiction was present. CONCLUSION: Opium tincture induced anti-propulsive effects in patients with chronic diarrhea refractory to standard treatment. This indicates that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea. Moreover, no evidence of opioid-induced sedation or addiction was found.Trial Registration Number: NCT05690321 (registered 2023-01-10).

Narcotic analgesics.

There is documentation of the use of opium derived products in the ancient history of the Assyrians: the Egyptians; in the sixth century AD by the Roman Dioscorides; and by Avicenna (980-1037). Reference to opium like products is made by Paracelsus and by Shakespeare. Charles Louis Derosne and Fredrich Wilhelm Adam Serturner isolated morphine from raw opium in 1802 and 1806 respectively, and it was Sertürner who named the substance morphine, after Morpheus, the Greek God of dreams. By the middle 1800s, Opium and related opioid derived products were the source of a major addiction in USA, and to some extent in the United Kingdom. Opioid products are of major therapeutic value in the treatment of pain from injury, post surgery, intractable pain conditions, and some forms of terminal cancer.

Blended smartphone intervention for patients in opioid maintenance treatment in Iran: protocol for a randomized controlled trial.

BACKGROUND: The pattern of substance use in Iran is characterized by a high prevalence of opioid use and opioid use disorder (OUD). Although opioid maintenance therapy (OMT) has been introduced in Iran, approximately 50% of people with opioid use disorder remain unreached. Moreover, psychosocial treatment of OUD and common mental health symptoms during OMT is limited. Digital interventions have been shown to improve psychological distress, depression, anxiety, and post-traumatic stress disorder symptoms. In addition, providing psychoeducation and risk reduction counseling to prevent communicable diseases like HIV and infectious hepatitis is common via the Internet. However, despite these promising advances, no smartphone intervention in OMT has been investigated for the treatment of OUD and common comorbid mental health symptoms. OBJECTIVE: We examine the effectiveness of adding a blended smartphone intervention based on community reinforcement approach, motivational interviewing- and cognitive behavioral therapy compared to OMT as usual that aims to improve OMT outcomes and addresses common mental health symptoms in OMT patients in Iran. METHOD: Adults with opioid dependence entering 8 treatment centers in Tehran, Iran will be randomly assigned to receive either OMT plus a smartphone intervention or OMT as usual. The primary outcomes will be the percentage of negative urine tests for illicit, non-prescribed use of opioids (opium, heroin, tramadol) and treatment retention. Secondary outcomes will include the longest period of abstinence from the illicit, non-prescribed use of opioids (opium, heroin, and tramadol) confirmed by urine samples, changes in communicable disease risk-taking behaviors, changes in stress and common mental health symptoms, and client satisfaction. Data analysis will follow the intention-to-treat principle and employ (generalized) linear mixed models. DISCUSSION: This study will provide substantial knowledge for designing effective blended interventions for OUD. Moreover, it will investigate if treatment retention and OMT-related outcomes and common mental health symptoms can be improved by adding a smartphone intervention to OMT. TRIAL REGISTRATION: https://en.irct.ir/trial/53578 .

Molecular and Epigenetic Aspects of Opioid Receptors in Drug Addiction and Pain Management in Sport.

Opioids are substances derived from opium (natural opioids). In its raw state, opium is a gummy latex extracted from Papaver somniferum. The use of opioids and their negative health consequences among people who use drugs have been studied. Today, opioids are still the most commonly used and effective analgesic treatments for severe pain, but their use and abuse causes detrimental side effects for health, including addiction, thus impacting the user's quality of life and causing overdose. The mesocorticolimbic dopaminergic circuitry represents the brain circuit mediating both natural rewards and the rewarding aspects of nearly all drugs of abuse, including opioids. Hence, understanding how opioids affect the function of dopaminergic circuitry may be useful for better knowledge of the process and to develop effective therapeutic strategies in addiction. The aim of this review was to summarize the main features of opioids and opioid receptors and focus on the molecular and upcoming epigenetic mechanisms leading to opioid addiction. Since synthetic opioids can be effective for pain management, their ability to induce addiction in athletes, with the risk of incurring doping, is also discussed.

Elevated serum lead levels in neonates born to mothers suffering from opiate use disorder.

BACKGROUND: This study was performed to investigate lead levels in neonates born to the mothers suffering from opiate use disorder (OUD) and the association of lead levels with the Apgar score. METHODS: The present cross-sectional study included 56 neonates who were referred to the neonatal ward of Amir-Al Momenin Hospital, Zabol. The neonates were divided into two groups: the neonates whose mothers suffered OUD and the control group. Data were collected using a researcher-prepared questionnaire, and blood lead level was determined using the atomic absorption method. Data were statistically analyzed. RESULTS: In all, 56 neonates (28 from OUD mothers and 28 from the control mothers) were included in this study. Among the women with OUD, 16 (57%) used inhaled opium, while 12 (43%) consumed opium orally. There was a significant difference regarding Apgar score (9.76 ± 2.11 versus. 7.11 ± 4.21; p = 0.02) and the neonate's blood lead level (2.33 ± 1.3 µg/dl versus 7.33 ± 5.9 µg/dl) between the control and OUD groups (p < 0.001). The odds ratio of abnormally elevated blood lead level rose with increasing duration of maternal opiate disorder for opiate usage durations of 3 to 5 years (adjusted odds ratio [OR] 42.82, 95% confidence interval [CI] 3.27-561, p = 0.004) and > 5 years (adjusted OR 45.5, 95% CI 2.97-698, p = 0.006). CONCLUSION: The results of this study suggested a significant relationship between maternal opium consumption during pregnancy and neonatal serum lead levels, as well as decreased neonatal Apgar score.

Cervical stitch (cerclage) in combination with other treatments for preventing spontaneous preterm birth in singleton pregnancies.

BACKGROUND: Preterm birth (PTB) remains the foremost global cause of perinatal morbidity and mortality. Thus, the prevention of spontaneous PTB still remains of critical importance. In an attempt to prevent PTB in singleton pregnancies, cervical cerclage, in combination with other treatments, has been advocated. This is because, cervical cerclage is an intervention that is commonly recommended in women with a short cervix at high risk of preterm birth but, despite this, many women still deliver prematurely, as the biological mechanism is incompletely understood. Additionally, previous Cochrane Reviews have been published on the effectiveness of cervical cerclage in singleton and multiple pregnancies, however, none has evaluated the effectiveness of using cervical cerclage in combination with other treatments. OBJECTIVES: To assess whether antibiotics administration, vaginal pessary, reinforcing or second cerclage placement, tocolytic, progesterone, or other interventions at the time of cervical cerclage placement prolong singleton gestation in women at high risk of pregnancy loss based on prior history and/or ultrasound finding of 'short cervix' and/or physical examination. History-indicated cerclage is defined as a cerclage placed usually between 12 and 15 weeks gestation based solely on poor prior obstetrical history, e.g. multiple second trimester losses due to painless dilatation. Ultrasound-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation for transvaginal ultrasound cervical length < 20 mm in a woman without cervical dilatation. Physical exam-indicated cerclage is defined as a cerclage placed usually between 16 and 23 weeks gestation because of cervical dilatation of one or more centimetres detected on physical (manual) examination. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (26 September 2019), and reference lists of retrieved studies. SELECTION CRITERIA: We included published, unpublished or ongoing randomised controlled trial (RCTs). Studies using a cluster-RCT design were also eligible for inclusion in this review but none were identified. We excluded quasi-RCTs (e.g. those randomised by date of birth or hospital number) and studies using a cross-over design. We also excluded studies that specified addition of the combination therapy after cervical cerclage because the woman subsequently became symptomatic. We included studies comparing cervical cerclage in combination with one, two or more interventions with cervical cerclage alone in singleton pregnancies. DATA COLLECTION AND ANALYSIS: Two review authors independently screened titles and abstracts of all retrieved articles, selected studies for inclusion, extracted data, assessed risk of bias, and evaluated the certainty of the evidence for this review's main outcomes. Data were checked for accuracy. Standard Cochrane review methods were used throughout. MAIN RESULTS: We identified two studies (involving a total of 73 women) comparing cervical cerclage alone to a different comparator. We also identified three ongoing studies (one investigating vaginal progesterone after cerclage, and two investigating cerclage plus pessary). One study (20 women), conducted in the UK, comparing cervical cerclage in combination with a tocolytic (salbutamol) with cervical cerclage alone in women with singleton pregnancy did not provide any useable data for this review. The other study (involving 53 women, with data from 50 women) took place in the USA and compared cervical cerclage in combination with a tocolytic (indomethacin) and antibiotics (cefazolin or clindamycin) versus cervical cerclage alone - this study did provide useable data for this review (and the study authors also provided additional data on request) but meta-analyses were not possible. This study was generally at a low risk of bias, apart from issues relating to blinding. We downgraded the certainty of evidence for serious risk of bias and imprecision (few participants, few events and wide 95% confidence intervals). Cervical cerclage in combination with an antibiotic and tocolytic versus cervical cerclage alone (one study, 50 women/babies) We are unclear about the effect of cervical cerclage in combination with antibiotics and a tocolytic compared with cervical cerclage alone on the risk of serious neonatal morbidity (RR 0.62, 95% CI 0.31 to 1.24; very low-certainty evidence); perinatal loss (data for miscarriage and stillbirth only - data not available for neonatal death) (RR 0.46, 95% CI 0.13 to 1.64; very low-certainty evidence) or preterm birth < 34 completed weeks of pregnancy (RR 0.78, 95% CI 0.44 to 1.40; very low-certainty evidence). There were no stillbirths (intrauterine death at 24 or more weeks). The trial authors did not report on the numbers of babies discharged home healthy (without obvious pathology) or on the risk of neonatal death. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to evaluate the effect of combining a tocolytic (indomethacin) and antibiotics (cefazolin/clindamycin) with cervical cerclage compared with cervical cerclage alone for preventing spontaneous PTB in women with singleton pregnancies. Future studies should recruit sufficient numbers of women to provide meaningful results and should measure neonatal death and numbers of babies discharged home healthy, as well as other important outcomes listed in this review. We did not identify any studies looking at other treatments in combination with cervical cerclage. Future research needs to focus on the role of other interventions such as vaginal support pessary, reinforcing or second cervical cerclage placement, 17-alpha-hydroxyprogesterone caproate or dydrogesterone or vaginal micronised progesterone, omega-3 long chain polyunsaturated fatty acid supplementation and bed rest.

Opium-Related Lead Toxicity: An Integrative Review and Case Series.

BACKGROUND: Restrictive regulations and the increased price of opioids have resulted in the addition of impurities to illicit opioids by drug dealers. Among the adulterants, lead salts are optimal agents to make packages heavier. Consequently, lead toxicity has emerged in the opioid-user population. OBJECTIVES: Our goal was to review the related literature and describe patients with common presentations of opioid-related lead poisoning to provide a basis to prepare optimal management. METHODS: A narrative review was performed aiming to study opioid lead poisoning. PubMed and Google Scholar databases were explored with two Medical Subject Heading terms, lead poisoning and substance-related disorders to find a broad but relevant spectrum of articles. Then, the reference lists within those articles were checked to upgrade our literature pool on this issue. RESULTS: Ultimately, among English-language articles, 16 were case series and case reports of patients with lead intoxication after opioid consumption. Data pertaining to disease characteristics, diagnosis, and treatment protocols were extracted. CONCLUSIONS: The clinical presentation of opioid lead intoxication can vary from rather asymptomatic to severely debilitating gastrointestinal or neurologic symptoms. The diagnosis is made by checking lead blood levels after obviating other critical diagnoses and should be considered in each drug user in endemic regions of opioid addiction, such as the Middle East. Management protocols are suggested to cover both features of opioid-related complications and lead toxicity.

Opioid Prescribing Can Be Reduced in Oral and Maxillofacial Surgery Practice.

PURPOSE: Pain management is one of the most critical aspects of practice in oral and maxillofacial surgery. The purpose of this study was to measure the change in strong (stronger than codeine 30 mg) opioid use after introducing the standardized protocol ("office protocol") designed for opioid-free postoperative pain management. MATERIALS AND METHODS: This is a retrospective cohort study of patients who had surgical procedures performed at the NorthShore Center for Oral and Facial Surgery (Gurnee, IL). Data of patients who underwent qualified surgical procedures and filled prescriptions for strong opioids before and after introduction of the office protocol were analyzed. The primary predictor variable was introduction of the office protocol. The primary outcome variable was filling of a strong opioid prescription that was correlated to pain control as assessed by patients. Age and gender distributions also were analyzed. Proportions and associated 95% confidence intervals were used to compare the number of hydrocodone or oxycodone (strong) prescriptions filled by patients during a 3-year interval. RESULTS: In March 2016, the office protocol for pain management, designed to decrease opioid use, was introduced. In 2015 (before introduction of the office protocol), 2,016 adult patients (15 to 85 yr old) underwent qualified surgical procedures at the author's practice, 1,184 (59%) of whom required and filled strong opioid prescriptions. In 2017 (2 yr after introduction of the office procedure) that number decreased to 19%, whereas the number of qualified surgical procedures performed remained relatively the same between the years. Postoperative pain control was not qualitatively measured but was assumed adequate and correlated with the filling of a strong opioid prescription or requiring a refill, which would be recorded as part of total prescriptions filled. CONCLUSION: A 3-fold decrease in hydrocodone or oxycodone prescription fill was seen at the 2-year interval. As alternatives, nonsteroidal anti-inflammatory drugs, acetaminophen, and a homeopathic recovery kit (Vega Recovery Kit, StellaLife, Glenview, IL) were used for pain management for patients undergoing various oral surgery procedures.

Effectiveness of a Pre-emptive Preoperative Belladonna and Opium Suppository on Postoperative Urgency and Pain After Ureteroscopy.

PURPOSE: Postoperative ureteroscopy patients can develop bladder spasms, complaints of pain, and the urgent need to void during emergence from anesthesia. Discomfort leads to patient agitation, resulting in a risk to patient safety. The purpose of this study was to determine the effectiveness of a preemptive preoperative belladonna and opium (B + O) suppository on postoperative bladder comfort, narcotic requirements, and length of stay of ureteroscopy patients. DESIGN: A prospective double-blind study was conducted. METHODS: Fifty adult outpatients scheduled for ureteroscopy were assigned to routine care or a B + O suppository immediately after anesthesia induction. Urinary urgency and pain were assessed every 15 minutes. FINDINGS: Urgency significantly decreased in the B+O group, with less than half reporting urgency at discharge. CONCLUSIONS: Pre-emptive preoperative administration of a B + O suppository before ureteroscopy results in decreased urinary urgency during the postoperative recovery. Pre-emptive preoperative interventions can result in positive outcomes before discharge.

Mortality from respiratory diseases associated with opium use: a population-based cohort study.

BACKGROUND: Recent studies have suggested that opium use may increase mortality from cancer and cardiovascular diseases. However, no comprehensive study of opium use and mortality from respiratory diseases has been published. We aimed to study the association between opium use and mortality from respiratory disease using prospectively collected data. METHODS: We used data from the Golestan Cohort Study, a prospective cohort study in northeastern Iran, with detailed, validated data on opium use and several other exposures. A total of 50 045 adults were enrolled from 2004 to 2008, and followed annually until June 2015, with a follow-up success rate of 99%. We used Cox proportional hazard regression models to evaluate the association between opium use and outcomes of interest. RESULTS: During the follow-up period, 331 deaths from respiratory disease were reported (85 due to respiratory malignancies and 246 due to non-malignant aetiologies). Opium use was associated with an increased risk of death from any respiratory disease (adjusted HR 95% CI 3.13 (2.42 to 4.04)). The association was dose-dependent with a HR of 3.84 (2.61 to 5.67) for the highest quintile of cumulative opium use versus never use (Ptrend<0.001). The HRs (95% CI) for the associations between opium use and malignant and non-malignant causes of respiratory mortality were 1.96 (1.18 to 3.25) and 3.71 (2.76 to 4.96), respectively. CONCLUSIONS: Long-term opium use is associated with increased mortality from both malignant and non-malignant respiratory diseases.

Randomized controlled trial of postoperative belladonna and opium rectal suppositories in vaginal surgery.

BACKGROUND: After vaginal surgery, oral and parenteral narcotics are used commonly for pain relief, and their use may exacerbate the incidence of sedation, nausea, and vomiting, which ultimately delays convalescence. Previous studies have demonstrated that rectal analgesia after surgery results in lower pain scores and less intravenous morphine consumption. Belladonna and opium rectal suppositories may be used to relieve pain and minimize side effects; however, their efficacy has not been confirmed. OBJECTIVE: We aimed to evaluate the use of belladonna and opium suppositories for pain reduction in vaginal surgery. MATERIALS AND METHODS: A prospective, randomized, double-blind, placebo-controlled trial that used belladonna and opium suppositories after inpatient or outpatient vaginal surgery was conducted. Vaginal surgery was defined as (1) vaginal hysterectomy with uterosacral ligament suspension or (2) posthysterectomy prolapse repair that included uterosacral ligament suspension and/or colporrhaphy. Belladonna and opium 16A (16.2/60 mg) or placebo suppositories were administered rectally immediately after surgery and every 8 hours for a total of 3 doses. Patient-reported pain data were collected with the use of a visual analog scale (at 2, 4, 12, and 20 hours postoperatively. Opiate use was measured and converted into parenteral morphine equivalents. The primary outcome was pain, and secondary outcomes included pain medication, antiemetic medication, and a quality of recovery questionnaire. Adverse effects were surveyed at 24 hours and 7 days. Concomitant procedures for urinary incontinence or pelvic organ prolapse did not preclude enrollment. RESULTS: Ninety women were randomly assigned consecutively at a single institution under the care of a fellowship-trained surgeon group. Demographics did not differ among the groups with mean age of 55 years, procedure time of 97 minutes, and prolapse at 51%. Postoperative pain scores were equivalent among both groups at each time interval. The belladonna and opium group used a mean of 57 mg morphine compared with 66 mg for placebo (P=.43) in 24 hours. Patient satisfaction with recovery was similar (P=.59). Antiemetic and ketorolac use were comparable among groups. Subgroup analyses of patients with prolapse and patients <50 years old did not reveal differences in pain scores. The use of belladonna and opium suppositories was uncomplicated, and adverse effects, which included constipation and urinary retention, were similar among groups. CONCLUSION: Belladonna and opium suppositories are safe for use after vaginal surgery. Belladonna and opium suppositories did not reveal lower pain or substantially lower narcotic use. Further investigation may be warranted to identify a population that may benefit optimally from belladonna and opium use.

Utility of opium seed extract tests in preventing hypersensitivity reactions during surgery.

BACKGROUND: Anaphylaxis during anaesthesia is fatal in 3-9% of patients and analgesics, including opioids, and is the second most common medicament-related cause, although the prevalence is underestimated. We recently found that patients may generate IgE antibodies to opium seeds. OBJECTIVES: To determine the diagnostic accuracy of specific antibodies to morphine, codeine, rocuronium and oil body and aqueous fractions of Papaver somniferum seeds in the diagnosis and prevention of allergy to opioids. METHODS: Patients with hypersensitivity reactions during surgery, and severe clinical allergy (pollen, tobacco), and illicit heroin users were selected. The sensitivity, specificity and predictive values of in vivo and in vitro diagnostic techniques including oil body and aqueous fractions of P. somniferum seeds were measured. RESULTS: We studied 203 patients, with mean age 35.1±17.1 and 200 healthy controls. Patients sensitised to heroin or with hypersensitivity reactions during surgery responded to P. somniferum seed tests. Of patients not known to be sensitised to opioids, the highest positivity was in patients sensitised to tobacco (p<0.001). Opium seed skin tests and IgE, especially the oil body fraction, were more sensitive (64.2%) and specific (98.4%) than morphine, codeine and rocuronium tests for opioid sensitivity. Pollen allergy was not a risk factor for sensitisation to morphine. CONCLUSIONS: Sensitivity to opioids and intraoperative anaphylaxis can be diagnosed by routine tests. IgE and skin tests for the oil body fraction of P. somniferum had the highest sensitivity for sensitisation to opioids.

The Opium Wars of China in the Nineteenth Century and America in the Twenty-First.

The Opium Wars of 1839-1843 and 1856-1860 revealed the devastating effects of narcotic addiction on the health of the body politic of China. The defeated Qing dynasty lost effective sovereignty to the British, leaving it helpless against more than 100 years of exploitation by the European powers, the United States, and Japan. Today we see the same risk posed by prescription narcotics and illegal opioids imported from China that can be seen as retribution for the "Century of Humiliation" nearly two centuries ago.

How to improve the surveillance of the Taliban ban's impact on European drug markets.

In April 2023, the Taliban banned poppy cultivation and the trade of all narcotics. This caused a 95% reduction in opium production. Usually, that would be good news. But there is a substantial worry: synthetic opioids might fill the void left by heroin. This is concerning because these drugs have led to health emergencies in areas where they are prevalent. This paper highlights the limitations of the current drug surveillance system in Europe and proposes improvements. It argues that reliance on secondary data is insufficient. Instead, we need to interview a sentinel group of people who inject drugs and adjust city-level sentinel systems, such as wastewater analysis, to specifically track the spread of synthetic opioids. Without these proactive steps, we risk only noticing a transition from heroin to synthetic opioids after it has occurred, with its harmful impacts already in place.

The first intravenous anaesthetic: how well was it managed and its potential realized?

Our speciality commonly traces its origin to a demonstration of the inhalation of ether by a patient undergoing surgery in Boston in 1846. Less well known is the demonstration of the i.v. injection of opium with alcohol into a dog in Oxford in 1656, leading to anaesthesia followed by full long-term recovery. After gaining i.v. access, a mixture of opium and alcohol was injected, resulting in a brief period of anaesthesia. After a period during which the dog was kept moving to assist recovery, a full recovery was made. Details from this momentous experiment allow us to compare the technique used with modern management. It is important to consider why there was a failure to translate the results into clinical practice and nearly 200 yr of potentially pain-free surgery. Possible factors include lack of equipment for i.v. access, lack of understanding of dose-response effects, and a climate of scientific discovery rather than clinical application. Given the current interest in total i.v. anaesthesia, it seems appropriate to identify its origins well before those of inhalation anaesthesia.

[The first labor analgesia with drug was already performed in late Meiji-Period (1868-1912): trace of opioid-scopolamine which was used in Akiko Yosano, back to its origins].

There have been some records of labor analgesia with intravenous or rectal anesthetics in early Showa-period (1926-1989). However, the author found that labor analgesia had been already attempted for some women in late Meiji-period (1868-1912). One of agents used was pantopon, a water-soluble opioid without serious respiratory depression as morphine. The drug was developed and produced in Germany. Some doctors applied this agent with scopolamine to labor analgesia in Europe. They also reported that this combination also conferred excellent analgesic effects without any serious complications in the mother and fetus. This combination was originally used for general surgery with inhaled anesthesia at that period. It remains uncertain how Japanese doctors got pantopon scopolamine from Germany.

Pain management: A deeper look at rural and urban nurses' perceptions and experiences.

PURPOSE: About 11.4 million individuals admitted to misusing an opioid in the past year. The purpose of this study was to determine if nurses' definitions of pain management differed by location, and to assess the challenges treating patients with pain management concerns. This study fills a gap by comparing quantitative and qualitative feedback from nurses on pain management concerns in their practice location. METHODS: Data were collected using an electronic survey emailed to licensed nurses across the United States. The mixed methods survey used multiple choice, select all that apply, and open-ended responses to gather data on nurses' perceptions of pain management. One hundred and eighty nurses completed the survey and were included in the study. Sixty-six percent practiced in an urban hospital. FINDINGS: Rural and urban nurses defined pain management as nonopioids and opioids. Seventy-one percent of urban nurses defined pain management as physical therapy compared to only 61% of rural nurses. Similarly, 62% of urban nurses identified homeopathic medicines and treatments as pain management techniques compared to 52% of rural nurses. From the qualitative data, 32% of rural nurses stated that patients with pain management concerns only want pain medications compared to 14% of urban nurses. CONCLUSIONS: Nurses have a critical position in and valuable perspective on the opioid epidemic. Rural communities are relatively disadvantaged in combatting the opioid epidemic. The finding that rural residents only want pain medication instead of alternative pain management options further challenges the country's rural health care workforce.

Opioid Use Disorder from Poppy Seed Tea Use: A Case Report.

BACKGROUND Unwashed or unprocessed poppy seeds may be an underrecognized substance that can lead to dependence, abuse, and an opioid use disorder. Poppy seeds can be purchased in an unwashed or unprocessed form, and these seeds can be contaminated with the opium alkaloids morphine, codeine, and thebaine on their surfaces. Poppy seeds that are commercially available, such as those used for baking and in other food products, are legal to purchase, as they do not contain the opium alkaloids on their seed coats. Purchase and possession of the unwashed or unprocessed seeds are not legal in the United States. These contaminated poppy seeds can then be put through a process in which they are washed, and the supernatant (tea) is collected and consumed to experience its intoxicating effect or for the treatment of pain or opioid withdrawal. CASE REPORT A 65-year-old man with a history of alcohol use disorder, cannabis use, and chronic pain began using this poppy seed tea for treatment of chronic pain after his provider had stopped prescribing opioid pain medications for him. He developed a dependence on the tea. He had reached out for assistance as it was his desire to stop using the poppy seed tea. The diagnosis of an opioid use disorder was made using the DSM-V criteria. He was successfully induced and maintained on a buprenorphine/naloxone product. CONCLUSIONS Poppy seeds in their unwashed and unprocessed form can be misused and could lead to an opioid use disorder. This disorder can be treated with buprenorphine/naloxone products.