How side effects can improve treatment efficacy: a randomized trial.

While treatment side effects may adversely impact patients, they could also potentially function as indicators for effective treatment. In this study, we investigated whether and how side effects can trigger positive treatment expectations and enhance treatment outcomes. In this pre-registered trial (DRKS00026648), 77 healthy participants were made to believe that they will receive fentanyl nasal sprays before receiving thermal pain in a controlled experimental setting. However, nasal sprays did not contain fentanyl, rather they either contained capsaicin to induce a side effect (mild burning sensation) or saline (inert). After the first session, participants were randomized to two groups and underwent functional MRI. One group continued to believe that the nasal sprays could contain fentanyl while the other group was explicitly informed that no fentanyl was included. This allowed for the independent manipulation of the side effects and the expectation of pain relief. Our results revealed that nasal sprays with a side effect lead to lower pain than inert nasal sprays without side effects. The influence of side effects on pain was dependent on individual beliefs about how side effects are related to treatment outcome, as well as on expectations about received treatment. Functional MRI data indicated an involvement of the descending pain modulatory system including the anterior cingulate cortex and the periaqueductal gray during pain after experiencing a nasal spray with side effects. In summary, our data show that mild side effects can serve as a signal for effective treatment thereby influencing treatment expectations and outcomes, which is mediated by the descending pain modulatory system. Using these mechanisms in clinical practice could provide an efficient way to optimize treatment outcome. In addition, our results indicate an important confound in clinical trials, where a treatment (with potential side effects) is compared to placebo.

Expiratory Muscle Activity Counteracts Positive End-Expiratory Pressure and Is Associated with Fentanyl Dose in Patients with Acute Respiratory Distress Syndrome.

Rationale: Hypoxemia during mechanical ventilation might be worsened by expiratory muscle activity, which reduces end-expiratory lung volume through lung collapse. A proposed mechanism of benefit of neuromuscular blockade in acute respiratory distress syndrome (ARDS) is the abolition of expiratory efforts. This may contribute to the restoration of lung volumes. The prevalence of this phenomenon, however, is unknown. Objectives: To investigate the incidence and amount of end-expiratory lung impedance (EELI) increase after the administration of neuromuscular blocking agents (NMBAs), clinical factors associated with this phenomenon, its impact on regional lung ventilation, and any association with changes in pleural pressure. Methods: We included mechanically ventilated patients with ARDS monitored with electrical impedance tomography (EIT) who received NMBAs in one of two centers. We measured changes in EELI, a surrogate for end-expiratory lung volume, before and after NMBA administration. In an additional 10 patients, we investigated the characteristic signatures of expiratory muscle activity depicted by EIT and esophageal catheters simultaneously. Clinical factors associated with EELI changes were assessed. Measurements and Main Results: We included 46 patients, half of whom showed an increase in EELI of >10% of the corresponding Vt (46.2%; IQR, 23.9-60.9%). The degree of EELI increase correlated positively with fentanyl dosage and negatively with changes in end-expiratory pleural pressures. This suggests that expiratory muscle activity might exert strong counter-effects against positive end-expiratory pressure that are possibly aggravated by fentanyl. Conclusions: Administration of NMBAs during EIT monitoring revealed activity of expiratory muscles in half of patients with ARDS. The resultant increase in EELI had a dose-response relationship with fentanyl dosage. This suggests a potential side effect of fentanyl during protective ventilation.

Effectiveness of opioid switching for dyspnea and its predictors in cancer patients: a single-center retrospective observational study.

BACKGROUND: Morphine is the most used opioid for dyspnea, but other opioids such as oxycodone and fentanyl are increasingly used, and opioid switching to these is sometimes undertaken. No studies have verified the effectiveness of opioid switching for relief of dyspnea. We retrospectively investigated the effectiveness of opioid switching for dyspnea and its predictors. METHODS: All patients with opioid switching for dyspnea during hospitalization at Komaki City Hospital from January 2019 to August 2022 were included. Opioid switching was defined as a change to another opioid, and the assessment period for evaluating the effectiveness and adverse events of opioid switching was set as 1 week. Patients with Numeric Rating Scale or Japanese version of the Support Team Assessment Schedule reduction for dyspnea of at least 1, or with clear improvement based on medical records, were considered valid. Mitigating factors for dyspnea were identified using logistic regression analysis. RESULTS: Of the 976 patients with opioid switching, 57 patients had opioid switching for relief of dyspnea. Of these, opioid switching was effective in 21 patients (36.8%). In a multivariate analysis, older patients (odds ratio: 5.52, 95% CI: 1.50-20.20, P < 0.01), short prognosis for post-opioid switching (odds ratio: 0.20, 95% CI: 0.04-0.87, P = 0.03) and cachexia (odds ratio: 0.12, 95% CI: 0.02-0.64, P < 0.01) were significantly associated with opioid switching effects for dyspnea. There were no serious adverse events after opioid switching. CONCLUSION: This study indicates that opioid switching for dyspnea may have some effect. Furthermore, opioid switching for dyspnea may be more effective in older patients and less effective in terminally ill patients or in those with cachexia.

A randomized controlled trial of propofol-remifentanil total intravenous anesthesia and sevoflurane-fentanyl anesthesia on early postoperative fatigue in patients undergoing laparoscopic colorectal surgery.

PURPOSE: Even after uncomplicated surgery, postoperative fatigue prevalence has been reported to be 30-80% for various surgeries. We evaluated postoperative fatigue according to anesthetic technique in patients who underwent colorectal surgery. METHODS: One hundred thirty patients who underwent colorectal surgery were randomly assigned to either propofol-remifentanil total intravenous anesthesia (propofol-remifentanil group, n = 65) or sevoflurane-fentanyl anesthesia (sevoflurane-fentanyl group, n = 65). The primary outcome was the prevalence of postoperative fatigue, as defined by the Chalder Fatigue Questionnaire (total score ≥ 16), at 24 h postoperatively. Secondary outcomes were early postoperative complications during hospitalization and laboratory examination. RESULTS: The final analyses included 127 patients. The prevalence of postoperative fatigue on the 1st postoperative day was lower in the propofol-remifentanil group than the sevoflurane-fentanyl group: 56.3% (36/64) in the propofol-remifentanil group and 73.0% (46/63) in the sevoflurane-fentanyl group (relative risk [RR] = 0.77, 95% confidence interval [CI] 0.59-1.00; P = 0.048). However, there was no difference between the two groups in postoperative fatigue at postoperative day 3. Other postoperative outcomes including the severity of pain and the incidence of nausea/vomiting were not different between the two groups, but postoperative atelectasis on chest X-ray was higher in the sevoflurane-fentanyl group (2/64 [3.1%] vs. 9/63 [14.3%], P = 0.025). C-reactive protein change from preoperative to postoperative day 1 and 5 was significantly lower in the propofol-remifentanil group (P = 0.044). CONCLUSION: Propofol-remifentanil total intravenous anesthesia was associated with reduced postoperative fatigue at the 1st postoperative day compared with sevoflurane-fentanyl anesthesia. Clinical trial The Korean Clinical Research Registry (study identifier: KCT0006917, principal investigator's name: MiHye Park, date of registration: January 12, 2022).

Open-label investigation of rapid initiation of extended-release buprenorphine in patients using fentanyl and fentanyl analogs.

BACKGROUND AND OBJECTIVES: Synthetic opioids, including fentanyl and fentanyl analogs, account for over 70,000 annual overdose deaths in the United States, but there is limited information examining methods of induction and maintenance outcomes for buprenorphine treatment of patients with opioid use disorder (OUD) using these opioids. METHODS: A secondary analysis of results grouped by fentanyl use status was completed for an open-label study with rapid induction of extended-release buprenorphine in the inpatient research unit. Eligible participants received a single 4 mg dose of transmucosal buprenorphine (BUP-TM) followed by an extended-release buprenorphine 300 mg injection ([BUP-XR]) after approximately 1 h. An extension study continued follow-up up to 6 months (6 monthly injections). RESULTS: Among participants with fentanyl-positive urine samples (FEN+; n = 19), all received BUP-TM, 17 received BUP-XR, 13 elected to receive a second BUP-XR injection, and 10 received all six scheduled injections. Among participants with fentanyl-negative samples (FEN-; n = 7), all received BUP-TM and BUP-XR, four elected to receive a second injection, and two participants received all six scheduled injections. Induction day clinical opioid withdrawal scale (COWS) scores were similar for FEN+ and FEN- groups. In the FEN+ group, mean COWS scores fell to below 5 within 24 h of BUP-XR injection. DISCUSSION AND CONCLUSIONS: The treatment of individuals with OUD using fentanyl with a rapid 1-day induction to BUP-XR 300 mg injection is feasible and well-tolerated. SCIENTIFIC SIGNIFICANCE: A prospective trial of participants grouped by fentanyl use status at induction demonstrates comparable patient retention and clinical response following single-day induction of BUP-XR in participants who are FEN+ and FEN-.

What is the Evidence for Using Intranasal Medicine in the Prehospital Setting? A Systematic Review.

OBJECTIVES: Intranasal (IN) medications offer a safe non-invasive way to rapidly deliver drugs in situations where intravenous (IV) access and intramuscular (IM) administration is challenging or not feasible. In the prehospital setting, this can be an essential alternative in time critical situations including trauma management, seizures, and agitated patients. However, there is a paucity of evidence summarizing its efficacy in this environment. This systematic review aims to assess the current evidence supporting the use of IN medicine (midazolam, ketamine, fentanyl, morphine, glucagon, and naloxone) in the prehospital setting alone. METHODS: A systematic literature search (PROSPERO CRD42023440713) of PubMed, Web of Science, OVID Medline, "Cochrane Central Register of Controlled Trials," Cochrane reviews and Embase was performed from inception to June 2023 to identify studies where IN medications were administered to patients in the prehospital setting. All randomized controlled trials, observational cohort studies, case series, and case reports were included. Papers not written in English, review articles, abstracts, and non-published data (including letters to the editor) were excluded. The methodological quality of the included studies was interpreted using the Cochrane risk of bias tool and rated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. No funding was received. RESULTS: From 4818 studies, 39 were included (seven for midazolam, five for ketamine, twelve for fentanyl, one for diamorphine, two for glucagon, and twelve for naloxone). A total of 24,097 patients were treated with IN medications across all the studies. There were five moderate quality, four low quality, and thirty very low quality studies. The potential efficacy of IN fentanyl and ketamine was demonstrated consistently throughout the studies with less clear evidence for midazolam, morphine, glucagon, and naloxone. This review was severely limited by the study quality, with most studies demonstrating "high concerns" for bias. CONCLUSIONS: Prehospital IN medication administration has wide-ranging potential, particularly for administering analgesia. There are likely to be certain populations, for example, pediatrics, that will benefit the most, although conclusions are limited by the quality of evidence currently available. We encourage additional research in this area, particularly with robust prospective double-blind RCTs.

Intravenous Ketamine for Pain Control in First-Trimester Surgical Abortion: Interim Analysis of a Randomized Controlled Trial.

OBJECTIVES: Surgical abortion is common, with most completed in the first trimester. Gold standard pain control is intravenous (IV) fentanyl and midazolam, requiring continuous cardio-respiratory monitoring, a potential challenge where this monitoring is unavailable. Ketamine is a sedative and analgesic without the cardio-respiratory depression risk associated with IV opioids, representing a potential alternative. Investigating non-opiate pain control methods is imperative given the context of the opioid crisis. This is an interim analysis of 45 participants from a randomized controlled trial comparing IV ketamine, oral morphine, and IV fentanyl for pain control in first-trimester surgical abortion. We hypothesize that ketamine will provide better pain control than morphine. METHODS: This is a double-blind, single-centre superiority trial of 3 parallel groups. Participants were ≥18 years old with confirmed intrauterine pregnancy of gestational age <12 weeks. Pain was assessed using the Visual Analogue Scale and the Wong-Baker Faces Pain Rating Scale. RESULTS: In total, 2 participants were excluded post-randomization for 43 treated. Findings indicate that ketamine (n = 14; M = 0.7; 95% CI 0.1-1.3) provides better intra-operative pain control than morphine (n = 15, M = 4.4, 95% CI 2.9-5.9) and fentanyl (n = 14; M = 4.3; 95% CI 3.0-5.6; P < 0.001). The ketamine group was more satisfied with the anaesthetic method than the morphine group (P = 0.017). No group experienced serious adverse events. CONCLUSIONS: Findings support continuation of the randomized controlled trial and highlight ketamine as a compelling non-opiate pain control option in first-trimester surgical abortion. Ketamine use may represent more optimal pain control in settings where continuous cardio-respiratory monitoring is unavailable.

Effectiveness of fentanyl buccal soluble film in cancer patients with inadequate breakthrough pain control.

BACKGROUND: Clinical evidence for the rapidity and effectiveness of fentanyl buccal soluble film (FBSF) in reducing pain intensity of breakthrough cancer pain (BTcP) remains inadequate. This study aimed to evaluate the efficacy of FBSF proportional to the around-the-clock (ATC) opioid regimens in rapidly relieving the intensity of BTcP episodes by determining the percentage of patients requiring further dose titration. METHODS: The study procedure included a dose-finding period followed by a 14-day observation period. Pain intensity was recorded with a Numeric Rating Scale (NRS) at onset and 5, 10, 15, and 30 min after FBSF self-administration. Meaningful pain relief was defined as the final NRS score ≤ 3. Satisfaction survey was conducted for each patient after treatment using the Global Satisfaction Scale. RESULTS: A total of 63 BTcP episodes occurred in 30 cancer patients. Only one patient required rescue medication at first BTcP episode and then achieved meaningful pain relief after titrating FBSF by 200 µg. Most BTcP episodes relieved within 10 min. Of 63 BTcP episodes, 30 (47.6%), 46 (73.0%), and 53 (84.1%) relieved within 5, 10, and 15 min after FBSF administration. Only grade 1/2 adverse events were reported, including somnolence, malaise, and dizziness. Of the 63 BTcP episodes, 82.6% were rated as excellent/good satisfaction with FBSF. CONCLUSION: FBSF can be administrated "on demand" by cancer patients at the onset of BTcP, providing rapid analgesia by achieving meaningful pain relief within 10 min. TRIAL REGISTRATION: This study was retrospectively registered 24 December, 2021 at Clinicaltrial.gov (NCT05209906): https://clinicaltrials.gov/study/NCT05209906 .

Opioid Use Disorder, Adolescents, and the Importance of Treatment in the Emergency Department.

ABSTRACT: Deaths from opiate overdoses are climbing every year, especially from fentanyl. Adolescents are particularly vulnerable to the acute and chronic harms associated with drug use, addiction, and overdose. Providers in the acute care setting have a unique opportunity to address a population of adolescents with opioid use disorder who are at the highest risk of harm and who may be more receptive to help. It is critical that providers are familiar with the tools that are available to assist and have some facility with their application.

Comparison of bupivacaine liposome injectable solution and fentanyl for postoperative analgesia in dogs undergoing limb amputation.

OBJECTIVE: The objectives of the study were to compare the clinical efficacy and adverse effects of two analgesic protocols consisting of bupivacaine liposome injectable solution (BLIS) and 0.5% bupivacaine and fentanyl for postsurgical analgesia in dogs undergoing limb amputation. STUDY DESIGN: Randomized, double-blind, prospective, controlled, intent-to-treat, clinical noninferiority trial. ANIMALS: Forty client-owned dogs. METHODS: Dogs undergoing amputation were randomly assigned to either the BLIS or control group. Postoperative pain, sedation, nausea, and amount eaten were assessed using appropriate scales at 6, 12, 18, and 24 h by trained individuals blinded to the treatment protocol. Rescue analgesia was provided for Glasgow composite measure pain scale (short form) (CMPS-SF) scores of 5 or above. Clients were requested to pain score their dogs at home using a visual analogue scale (VAS) for 48 h following discharge. RESULTS: Forty dogs completed this study (20 control dogs and 20 BLIS dogs). The BLIS and control groups were equivalent for sedation, nausea, amount eaten, and pain, at all time periods except at 6 h (p < .01), when the BLIS group pain score was lower. CONCLUSION: The BLIS provided equivalent analgesia with fewer adverse effects than fentanyl constant rate infusion (CRI) following limb amputation. Rescue analgesia was provided to five dogs in the BLIS group and four in the control group, and there was no statistical difference. Nausea scores did not differ statistically. CLINICAL SIGNIFICANCE: As BLIS provides equivalent analgesia, this may allow for decreased reliance on opioids in the immediate postoperative period.

Perioperative analgesic effects of the erector spinae plane block with bupivacaine or bupivacaine-dexmedetomidine in dogs undergoing hemilaminectomy: A randomized controlled trial.

Objective: To compare the perioperative opioid requirements among dogs receiving an erector spinae plane (ESP) block with bupivacaine, with or without dexmedetomidine, and a control group. Animals and procedure: Thirty client-owned, healthy adult dogs undergoing hemilaminectomy were included in this randomized, prospective, blinded clinical study. Dogs were randomly assigned to 1 of 3 treatment groups: Group B, ESP block with bupivacaine; Group BD, ESP block with bupivacaine and dexmedetomidine; and Group C, control. Rescue intra- and postoperative analgesia consisted of fentanyl and methadone, respectively. Postoperative pain was evaluated using the short form of the Glasgow Composite Measure Pain Scale (CMPS-SF). Results: In Group BD, 0/10 dogs required intraoperative fentanyl, compared to 9/10 in Group C (P < 0.001), whereas 1/10 required postoperative methadone, compared to 9/10 in Group B (P = 0.003) and 10/10 in Group C (P < 0.001). The total amount of intraoperative fentanyl (µg/kg) was 0 (0 to 4) in Group B and 0 (0 to 0) in BD, compared to 6 (0 to 8) in C (P = 0.004 and P < 0.001, respectively). Postoperative methadone (mg/kg) required during the first 12 h was 0.5 (0 to 1.4) in Group B (P = 0.003) and 0 (0 to 0) in BD (P < 0.001), compared to C (P = 0.003 and P < 0.001, respectively). Conclusion: An ESP block with bupivacaine, with or without dexmedetomidine, was associated with a reduction in perioperative opioid consumption and provided effective acute pain control.

Effets analgésiques périopératoires du bloc des érecteurs du rachis avec de la bupivacaïne ou de la bupivacaïne-dexmédétomidine chez les chiens subissant une hémilaminectomie: un essai contrôlé randomisé. Objectif: Comparer les besoins périopératoires en opioïdes chez les chiens recevant un bloc des érecteurs de la colonne vertébrale (ESP) avec de la bupivacaïne, avec ou sans dexmédétomidine, et un groupe témoin. Animaux et procédure: Trente chiens adultes en bonne santé appartenant à des clients subissant une hémilaminectomie ont été inclus dans cette étude clinique randomisée, prospective et en aveugle. Les chiens ont été répartis au hasard dans 1 des 3 groupes de traitement: groupe B, bloc ESP avec bupivacaïne; groupe BD, bloc ESP avec bupivacaïne et dexmédétomidine; et groupe C, témoin. L'analgésie de secours peropératoire et postopératoire consistait respectivement en fentanyl et en méthadone. La douleur postopératoire a été évaluée à l'aide du formulaire abrégé de l'échelle de mesure de la douleur de Glasgow (CMPS-SF). Résultats: Dans le groupe BD, 0/10 chiens ont eu besoin de fentanyl peropératoire, contre 9/10 dans le groupe C (P < 0,001), tandis que 1/10 ont eu besoin de méthadone postopératoire, contre 9/10 dans le groupe B (P = 0,003) et 10/10 dans le groupe C (P < 0,001). La quantité totale de fentanyl peropératoire (µg/kg) était de 0 (0 à 4) dans le groupe B et de 0 (0 à 0) dans le groupe BD, contre 6 (0 à 8) dans le groupe C (P = 0,004 et P < 0,001, respectivement). La méthadone postopératoire (mg/kg) nécessaire au cours des 12 premières heures était de 0,5 (0 à 1,4) dans le groupe B (P = 0,003) et de 0 (0 à 0) dans le groupe BD (P < 0,001), par rapport au groupe C (P = 0,003). et P < 0,001, respectivement). Conclusion: Un bloc ESP avec de la bupivacaïne, avec ou sans dexmédétomidine, a été associé à une réduction de la consommation peropératoire d'opioïdes et a permis un contrôle efficace de la douleur aiguë.(Traduit par Dr Serge Messier).

Finding predictors for successful opioid response in cancer patients: An analysis of data from four randomized controlled trials.

CONTEXT: There is no consensus on which "strong" (or step 3 WHO analgesic ladder) opioid to prescribe to a particular patient with cancer-related pain. A better understanding of opioid and patient characteristics on treatment response will contribute to a more personalized opioid treatment. OBJECTIVES: Assessment of potential predictors for successful opioid treatment response in patients with cancer pain. METHODS: An international partnership between four cancer pain research groups resulted in a combined individual-level database from four relevant randomized controlled trials (RCTs; n = 881). Together, these RCTs investigated the short-term (1 week) and medium-term (4 or 5 weeks) treatment responses for morphine, buprenorphine, methadone, oxycodone, and fentanyl. Candidate predictors for treatment response were sex, age, pain type, pain duration, depression, anxiety, Karnofsky performance score, opioid type, and use of anti-neuropathic drug. RESULTS: Opioid type and pain type were found statistically significant predictors of short-term treatment success. Sex, age, pain type, anxiety, and opioid type were statistically, significantly associated with medium-term treatment success. However, these models showed low discriminative power. CONCLUSION: Fentanyl and methadone, and mixed pain were found to be statistically significant predictors of treatment success in patients with cancer-related pain. With the predictors currently assessed our data did not allow for the creation of a clinical prediction model with good discriminative power. Additional - unrevealed - predictors are necessary to develop a future prediction model.

Self-Adjuvanting TLR7/8 Agonist and Fentanyl Hapten Co-Conjugate Achieves Enhanced Protection against Fentanyl Challenge.

Currently approved pharmacotherapies for opioid use disorders (OUDs) and overdose reversal agents are insufficient to slow the spread of OUDs due to the proliferation of fentanyl. This is evident in the 31% rise in drug overdose deaths from 2019 to 2022, with rates increasing from 21.6 to 28.3 overdoses per 100,000 deaths. Vaccines are a potential alternative or adjunct therapy for the treatment of several substance use disorders (nicotine, cocaine) but have shown limited clinical success due to suboptimal antibody titers. In this study, we demonstrate that coconjugation of a Toll-like receptor 7/8 (TLR7/8) agonist (UM-3006) alongside a fentanyl-based hapten (F1) on the surface of the carrier protein cross-reactive material 197 (CRM) significantly increased generation of high-affinity fentanyl-specific antibodies. This demonstrated enhanced protection against fentanyl challenges relative to an unconjugated (admix) adjuvant control in mice. Inclusion of aluminum hydroxide (alum) adjuvant further increased titers and enhanced protection, as determined by analysis of fentanyl concentration in serum and brain tissue. Collectively, our findings present a promising approach to enhance the efficacy of antiopioid vaccines, underscoring the need for extensive exploration of TLR7/8 agonist conjugates as a compelling strategy to combat opioid use disorders.

Comparison between ketorolac- and fentanyl-based patient-controlled analgesia for acute kidney injury after robot-assisted radical prostatectomy: a retrospective propensity score-matched analysis.

PURPOSE: It is unclear whether ketorolac-based patient-controlled analgesia (PCA) leads to acute kidney injury (AKI) after robot-assisted radical prostatectomy (RARP) in patients susceptible to AKI. We compared the postoperative AKI incidence with ketorolac- and fentanyl-based PCA after RARP. METHODS: After medical record review, eligible patients were divided in ketorolac and fentanyl groups. We conducted propensity score matching of 3239 patients and assigned 641 matched patients to each group, and compared the AKI incidence. We investigated potential risk factors for postoperative AKI, defined according to the Kidney Disease Improving Global Outcomes criteria. We collected preoperative data (age, height, weight, body mass index, American Society of Anesthesiologists physical status, medical history, creatinine level, estimated glomerular filtration rate, and hemoglobin level) and intraoperative data (maintenance anesthetics, surgery duration, anesthesia duration, crystalloid amount, colloid use, total amount of fluid administered, estimated blood loss, norepinephrine use, phenylephrine use, and PCA type). RESULTS: The postoperative AKI incidence was significantly higher in the ketorolac than in the fentanyl group, both before (31.1% vs. 20.4%; p < 0.001) and after (31.5% vs. 22.6%; p < 0.001) matching. In the univariate analysis, ketorolac was significantly associated with postoperative AKI, both before (odds ratio [OR], 1.762; 95% confidence interval [CI], 1.475-2.105; p < 0.001) and after (OR, 1.574; 95% CI, 1.227-2.019; p < 0.001) matching. In the multivariate analysis, ketorolac-based PCA was independently associated with development of postoperative AKI in the matched groups (OR, 1.659; 95% CI, 1.283-2.147; p < 0.001). CONCLUSION: Ketorolac-based PCA may increase postoperative AKI incidence after RARP; thus, renal function should be monitored in these patients.

The United States opioid crisis: Big pharma alone is not to blame."

OBJECTIVE: The opioid crisis in the United States continues essentially unabated, fueled by fentanyl contamination of the heroin supply and resulting in 79,770 reported opioid-involved overdose deaths in the calendar year 2022. To prevent another such crisis emerging, it is necessary to fully identify its root causes. METHODS: Despite the well-recognized role the pharmaceutical industry played in facilitating the crisis via the aggressive marketing of prescription opioids, several other less appreciated but perhaps more influential factors were also contributors, and the overall goal of this review is to ensure that these are not be lost to history in a concerted effort to blame opioid manufacturers and distributors. Presented is a historical review of research and regulatory documents beginning with the loosening of opioid prescription for chronic pain through current thought and practice today. Beginning with a necessary decoupling of the current opioid crisis from the increased use of opioids to treat chronic pain, this review will examine these contributing factors. RESULTS: Clinical concerns about under- or untreated pain, practice guidelines from standard-setting organizations and government entities, and a health system-wide move away from specialty interdisciplinary pain programs together set the stage for an over-reliance on opioids in chronic pain care. CONCLUSIONS: This review reminds the health care community that despite the deep pockets of the pharmaceutical industry and highly the organized efforts of the drug cartels, additional self-reflection is warranted to fully understand the true root causes of the current epidemic and ways to prevent similar epidemics in the future.

Efficacy of Continuous Intrathecal Infusion Trialing with a Mixture of Fentanyl and Bupivacaine in Chronic Low Back Pain Patients.

Intrathecal trialing is used as a screening prognostic measure prior to intrathecal drug delivery system implant. The purpose of this study was to determine the efficacy of a continuous intrathecal infusion of an admixture of bupivacaine and fentanyl in patients with chronic low back pain. Patients with refractory chronic low back pain in the setting of previous lumbar spine surgery and/or chronic vertebral compression fracture(s) were enrolled in a randomized double blind cross-over study comparing saline infusion to infusion of a solution containing bupivacaine combined with low-dose fentanyl over a 14-18 hour period. The primary outcome measure was the change in pain intensity at the end of the screening trial. Patients who experienced significant pain reduction from either infusion relative to baseline pain were offered a permanent implant. In total, 36 patients were enrolled, with 31 patients trialed and 25 implanted. At the end of the screening trial, pain scores, at rest or with activity, decreased appreciably in both groups; however, significantly better improvements occurred in the fentanyl/bupivacaine group compared to saline both with activity and at rest (P = .016 and .006, respectively). Treatment order appeared to affect outcome with saline demonstrating a placebo response. At 12 months following implant, primary and secondary outcome measures continued to be significantly reduced from baseline. Continuous intrathecal delivery of a combination of zlow-dose fentanyl with bupivacaine is superior to saline in screening intrathecal trialing for back pain reduction. With longer term delivery, a sustained reduction of chronic low back pain was also observed.

Opioids for procedural pain in neonates.

BACKGROUND: Neonates might be exposed to numerous painful procedures due to diagnostic reasons, therapeutic interventions, or surgical procedures. Options for pain management include opioids, non-pharmacological interventions, and other drugs. Morphine, fentanyl, and remifentanil are the opioids most often used in neonates. However, negative impact of opioids on the structure and function of the developing brain has been reported. OBJECTIVES: To evaluate the benefits and harms of opioids in term or preterm neonates exposed to procedural pain, compared to placebo or no drug, non-pharmacological intervention, other analgesics or sedatives, other opioids, or the same opioid administered by a different route. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was December 2021. SELECTION CRITERIA: We included randomized controlled trials conducted in preterm and term infants of a postmenstrual age (PMA) up to 46 weeks and 0 days exposed to procedural pain where opioids were compared to 1) placebo or no drug; 2) non-pharmacological intervention; 3) other analgesics or sedatives; 4) other opioids; or 5) the same opioid administered by a different route. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were pain assessed with validated methods and any harms. We used a fixed-effect model with risk ratio (RR) for dichotomous data and mean difference (MD) for continuous data, and their confidence intervals (CI). We used GRADE to assess the certainty of the evidence for each outcome. MAIN RESULTS: We included 13 independent studies (enrolling 823 newborn infants): seven studies compared opioids to no treatment or placebo (the main comparison in this review), two studies to oral sweet solution or non-pharmacological intervention, and five studies (of which two were part of the same study) to other analgesics and sedatives. All studies were performed in a hospital setting. Opioids compared to placebo or no drug Compared to placebo, opioids probably reduce pain score assessed with the Premature Infant Pain Profile (PIPP)/PIPP-Revised (PIPP-R) scale during the procedure (MD -2.58, 95% CI -3.12 to -2.03; 199 participants, 3 studies; moderate-certainty evidence); may reduce Neonatal Infant Pain Scale (NIPS) during the procedure (MD -1.97, 95% CI -2.46 to -1.48; 102 participants, 2 studies; low-certainty evidence); and may result in little to no difference in pain score assessed with the Douleur Aiguë du Nouveau-né (DAN) scale one to two hours after the procedure (MD -0.20, 95% CI -2.21 to 1.81; 42 participants, 1 study; low-certainty evidence). The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R scale up to 30 minutes after the procedure (MD 0.14, 95% CI -0.17 to 0.45; 123 participants, 2 studies; very low-certainty evidence) or one to two hours after the procedure (MD -0.83, 95% CI -2.42 to 0.75; 54 participants, 2 studies; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of bradycardia (RR 3.19, 95% CI 0.14 to 72.69; 172 participants, 3 studies; very low-certainty evidence). Opioids may result in an increase in episodes of apnea compared to placebo (RR 3.15, 95% CI 1.08 to 9.16; 199 participants, 3 studies; low-certainty evidence). The evidence is very uncertain about the effect of opioids on episodes of hypotension (RR not estimable, risk difference 0.00, 95% CI -0.06 to 0.06; 88 participants, 2 studies; very low-certainty evidence). No studies reported parent satisfaction with care provided in the neonatal intensive care unit (NICU). Opioids compared to non-pharmacological intervention The evidence is very uncertain about the effect of opioids on pain score assessed with the Crying Requires oxygen Increased vital signs Expression Sleep (CRIES) scale during the procedure when compared to facilitated tucking (MD -4.62, 95% CI -6.38 to -2.86; 100 participants, 1 study; very low-certainty evidence) or sensorial stimulation (MD 0.32, 95% CI -1.13 to 1.77; 100 participants, 1 study; very low-certainty evidence). The other main outcomes were not reported. Opioids compared to other analgesics or sedatives The evidence is very uncertain about the effect of opioids on pain score assessed with the PIPP/PIPP-R during the procedure (MD -0.29, 95% CI -1.58 to 1.01; 124 participants, 2 studies; very low-certainty evidence); up to 30 minutes after the procedure (MD -1.10, 95% CI -2.82 to 0.62; 12 participants, 1 study; very low-certainty evidence); and one to two hours after the procedure (MD -0.17, 95% CI -2.22 to 1.88; 12 participants, 1 study; very low-certainty evidence). No studies reported any harms. The evidence is very uncertain about the effect of opioids on episodes of apnea during (RR 3.27, 95% CI 0.85 to 12.58; 124 participants, 2 studies; very low-certainty evidence) and after the procedure (RR 2.71, 95% CI 0.11 to 64.96; 124 participants, 2 studies; very low-certainty evidence) and on hypotension (RR 1.34, 95% CI 0.32 to 5.59; 204 participants, 3 studies; very low-certainty evidence). The other main outcomes were not reported. We identified no studies comparing different opioids (e.g. morphine versus fentanyl) or different routes for administration of the same opioid (e.g. morphine enterally versus morphine intravenously). AUTHORS' CONCLUSIONS: Compared to placebo, opioids probably reduce pain score assessed with PIPP/PIPP-R scale during the procedure; may reduce NIPS during the procedure; and may result in little to no difference in DAN one to two hours after the procedure. The evidence is very uncertain about the effect of opioids on pain assessed with other pain scores or at different time points. No studies reported if any harms occurred. The evidence is very uncertain about the effect of opioids on episodes of bradycardia or hypotension. Opioids may result in an increase in episodes of apnea. No studies reported parent satisfaction with care provided in the NICU. The evidence is very uncertain about the effect of opioids on any outcome when compared to non-pharmacological interventions or to other analgesics. We identified no studies comparing opioids to other opioids or comparing different routes of administration of the same opioid.

Non-opioid analgesics for procedural pain in neonates.

BACKGROUND: Neonates are an extremely vulnerable patient population, with 6% to 9% admitted to the neonatal intensive care unit (NICU) following birth. Neonates admitted to the NICU will undergo multiple painful procedures per day throughout their stay. There is increasing evidence that frequent and repetitive exposure to painful stimuli is associated with poorer outcomes later in life. To date, a wide variety of pain control mechanisms have been developed and implemented to address procedural pain in neonates. This review focused on non-opioid analgesics, specifically non-steroidal anti-inflammatory drugs (NSAIDs) and N-methyl-D-aspartate (NMDA) receptor antagonists, which alleviate pain through inhibiting cellular pathways to achieve analgesia.  The analgesics considered in this review show potential for pain relief in clinical practice; however, an evidence summation compiling the individual drugs they comprise and outlining the benefits and harms of their administration is lacking. We therefore sought to summarize the evidence on the level of pain experienced by neonates both during and following procedures; relevant drug-related adverse events, namely episodes of apnea, desaturation, bradycardia, and hypotension; and the effects of combinations of drugs.  As the field of neonatal procedural pain management is constantly evolving, this review aimed to ascertain the scope of non-opioid analgesics for neonatal procedural pain to provide an overview of the options available to better inform evidence-based clinical practice.  OBJECTIVES: To determine the effects of non-opioid analgesics in neonates (term or preterm) exposed to procedural pain compared to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration. SEARCH METHODS: We searched the Cochrane Library (CENTRAL), PubMed, Embase, and two trial registries in June 2022. We screened the reference lists of included studies for studies not identified by the database searches. SELECTION CRITERIA: We included all randomized controlled trials (RCTs), quasi-RCTs, and cluster-RCTs in neonates (term or preterm) undergoing painful procedures comparing NSAIDs and NMDA receptor antagonists to placebo or no drug, non-pharmacological intervention, other analgesics, or different routes of administration.  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our main outcomes were pain assessed during the procedure and up to 10 minutes after the procedure with a validated scale; episodes of bradycardia; episodes of apnea; and hypotension requiring medical therapy. MAIN RESULTS: We included two RCTs involving a total of 269 neonates conducted in Nigeria and India.  NMDA receptor antagonists versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention One RCT evaluated using oral ketamine (10 mg/kg body weight) versus sugar syrup (66.7% w/w at 1 mL/kg body weight) for neonatal circumcision.  The evidence is very uncertain about the effect of ketamine on pain score during the procedure, assessed with the Neonatal Infant Pain Scale (NIPS), compared with placebo (mean difference (MD) -0.95, 95% confidence interval (CI) -1.32 to -0.58; 1 RCT; 145 participants; very low-certainty evidence). No other outcomes of interest were reported on. Head-to-head comparison of different analgesics One RCT evaluated using intravenous fentanyl versus intravenous ketamine during laser photocoagulation for retinopathy of prematurity. Neonates receiving ketamine followed an initial regimen (0.5 mg/kg bolus 1 minute before procedure) or a revised regimen (additional intermittent bolus doses of 0.5 mg/kg every 10 minutes up to a maximum of 2 mg/kg), while those receiving fentanyl followed either an initial regimen (2 µg/kg over 5 minutes, 15 minutes before the procedure, followed by 1 µg/kg/hour as a continuous infusion) or a revised regimen (titration of 0.5 µg/kg/hour every 15 minutes to a maximum of 3 µg/kg/hour). The evidence is very uncertain about the effect of ketamine compared with fentanyl on pain score assessed with the Premature Infant Pain Profile-Revised (PIPP-R) scores during the procedure (MD 0.98, 95% CI 0.75 to 1.20; 1 RCT; 124 participants; very low-certainty evidence); on episodes of apnea occurring during the procedure (risk ratio (RR) 0.31, 95% CI 0.08 to 1.18; risk difference (RD) -0.09, 95% CI -0.19 to 0.00; 1 study; 124 infants; very low-certainty evidence); and on hypotension requiring medical therapy occurring during the procedure (RR 5.53, 95% CI 0.27 to 112.30; RD 0.03, 95% CI -0.03 to 0.10; 1 study; 124 infants; very low-certainty evidence). The included study did not report pain score assessed up to 10 minutes after the procedure or episodes of bradycardia occurring during the procedure. We did not identify any studies comparing NSAIDs versus no treatment, placebo, oral sweet solution, or non-pharmacological intervention or different routes of administration of the same analgesics. We identified three studies awaiting classification.  AUTHORS' CONCLUSIONS: The two small included studies comparing ketamine versus either placebo or fentanyl, with very low-certainty evidence, rendered us unable to draw meaningful conclusions. The evidence is very uncertain about the effect of ketamine on pain score during the procedure compared with placebo or fentanyl. We found no evidence on NSAIDs or studies comparing different routes of administration. Future research should prioritize large studies evaluating non-opioid analgesics in this population. As the studies included in this review suggest potential positive effects of ketamine administration, studies evaluating ketamine are of interest. Furthermore, as we identified no studies on NSAIDs, which are widely used in older infants, or comparing different routes of administration, such studies should be a priority going forward.

IF IM in a crisis: Intranasal fentanyl versus intravenous morphine in adult vaso-occlusive crisis.

IMPORTANCE: Studies have demonstrated the benefits of INF in reducing pain scores in pediatric patients with VOC due to sickle cell disease (SCD) and in adult patients with chronic pain conditions other than VOC, such as cancer. However, there is limited literature that exists describing the role of INF in adult patients with VOC due to SCD. Current literature demonstrates that the use of IV morphine for VOC patients leads to reduced pain. Therefore, comparing the use of INF with IV morphine will establish the degree of effectiveness of INF for VOC patients. OBJECTIVE: To determine if intranasal fentanyl is equally as effective as IV morphine for treating VOC-associated pain in adult SCD patients. DESIGN: This study was a retrospective non-inferiority cohort study. Electronic health records were utilized to identify eligible patients between January 1, 2021 to February 28, 2022. Patients who received INF as an initial opioid upon presentation to the ED where allocated to the intervention group. On the other hand, individuals who received IV morphine as an initial opioid upon presentation to the ED were allocated to the control group. SETTING: A multi-site healthcare system containing five hospitals. PARTICIPANTS: Patients 18 years of age or older, admitted to the ED with VOC due to SCD, and received INF or IV morphine as an initial opioid upon presentation to the ED. MAIN OUTCOMES AND MEASURES: The primary outcome was to evaluate the percent change in pain reduction after the initial dose of opiate between groups. Secondary outcomes include time to first rescue medication, total morphine milligram equivalent (MME) of IV opiates, hypotension, bradycardia, respiratory distress requiring opiate reversal within 6 h post- study drug administration, readmission within 48 h, and ED disposition. RESULTS: A total of 230 patients were reviewed within the study period, 95 subjects met inclusion criteria, 31 subjects were included in the INF arm and 64 subjects in the IV morphine arm. The primary outcome showed an average percent pain reduction of 17.25% in the INF arm and 17.15% in the IV morphine arm. The point estimate difference was 0.1% (95% CI -9.3%-9.5%; non-inferiority (p < 0.0001). The median dose of IV opiates was 8 MME in the INF group, and 6 MME in the IV morphine group (p = 0.0268). The time from study drug to first rescue medication administration was 22.4 min and 27.3 min in the INF and IV morphine groups, respectively (p = 0.2231). There was no incidence of hypotension or respiratory distress requiring opiate reversal in either arm. Bradycardia occurred in 12.9% and 7.7% (p = 0.2042), readmission rates within 48 h due to VOC was 6.5% and 20.9% (p = 0.0553), and discharge from the ED to home was 16% and 66% (p = 0.0196) in INF and IV morphine arms, respectively. CONCLUSION: INF provided similar pain reduction compared to IV morphine in the treatment of adults with VOC presenting to the ED. IV morphine arm showed a statistically significant difference in discharge to home from the ED, however there was a trend in readmission within 48 h. The study showed no significant difference in hypotension, respiratory distress, or bradycardia between the groups. The INF group had no significant impact on time to drug administration compared to IV morphine, however it was within 1 h of patient presentation which complies with American Society of Hematology (ASH) guidelines. In conclusion, our study showed that INF was non-inferior when compared to IV morphine in reducing pain scores after drug administration. Therefore, INF is an effective alternative to IV morphine for pain management in adults presenting to the ED for VOC particularly in those with limited IV access.

Does the combination of intrathecal fentanyl and morphine improve clinical outcomes in patients undergoing lumbar fusions?

Intrathecal morphine (ITM) has been widely effective in improving postoperative outcomes in patients undergoing a multitude of surgeries, including lumbar spine fusion. A major limitation of ITM administration is the increase in the incidence of respiratory depression in a dose-dependent manner. One way to bypass this is to use a more potent opioid with a shorter half-life, such as fentanyl. This is a retrospective analysis of patients who underwent one- or two-level transforaminal lumbar interbody fusions. The patients received one of two interventions: 0.2mg intrathecal duramorph/morphine (ITM group; n=70), 0.2mg duramorph + 50 mcg fentanyl (ITM + fentanyl group; n=68) and the control group (n=102). Primary outcomes included postoperative pain (Visual Analog Scale) and opioid intake (MED - morphine equivalent dosage, mg) for postoperative days (POD) 1- 4. Secondary outcomes included opioid-related side effects. One-way analyses of variance and follow-up post-hoc Tukey's honest significant difference statistical tests were used to measure treatment effects. Significantly lower POD1 pain scores for both the ITM and ITM + fentanyl groups vs. control were detected, with no difference between the ITM vs. ITM + fentanyl groups. Similar results were found for POD1 MED intake. A multivariate regression analysis controlling for confounding variables did not attenuate the differences seen in POD1 pain scores while revealing that only the ITM + fentanyl predicted a decrease in POD1 MED intake. No differences were seen for postoperative opioid-related side effects. Our study provides support for supplementing a low dose of both intrathecal morphine and fentanyl to improve postoperative outcomes.