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Background: Opioids remain the mainstay of cancer pain management but are associated with systemic toxicity. In refractory cancer pain, intrathecal therapy (ITT) is associated with improved pain control, reduced systemic side effects, and improved survival. It has been assumed that ITT decreases systemic serum opioid levels and their associated toxicity, but there are limited data to support this assumption. This study hypothesizes that serum opioid levels decrease with ITT. Secondary objectives include comparative measures of pain, bowel function, and other cancer-related symptoms., Methods: Fifty-one cancer patients undergoing ITT for cancer pain were recruited in a prospective observational study. Daily oral morphine equivalency (OME) dose, serum opioid levels, Brief Pain Inventory (BPI), MD Anderson Symptom Inventory (MDASI), and a constipation questionnaire were obtained at the time of implant, and 4 and 8 weeks postoperatively., Results: Average baseline daily OME was 375 mg (median, 240; interquartile range, 150-405; range, 0-3160), mean serum morphine concentration was 53.7 ng/mL (n = 17), and mean oxycodone concentration was 73.7 ng/mL (n = 20). At 4 weeks, 87.5% of patients had discontinued non-IT opioids, and 53% had undetectable (<2 ng/mL) serum opioid concentrations. At 8 weeks, 92% remained off all non-IT opioids and 59% had undetectable serum opioid levels. IT morphine doses >4.2 mg/d were invariably associated with detectable serum levels; with doses <4.2 mg, morphine was undetectable in 80% of subjects. IT hydromorphone doses >6.8 mg/d were detectable in the serum. Using linear mixed model analyses, there were statistically significant decreases in the mean "worst pain," "average pain," and MD Anderson symptom severity and interference scores at 4 and 8 weeks. This change was independent of serum opioid levels; when analyzed separately, there was no difference in the pain scores of subjects with detectable serum opioid levels compared to those with undetectable levels at 4 and 8 weeks. Constipation ranked as "quite a bit" or "very much" decreased from 58.7% to 19.2% of subjects at week 4 (P < .001) and to 37.5% at 8 weeks (P = .23). A very low complication rate was observed., Conclusions: ITT for cancer pain was associated with a marked reduction in serum opioid concentrations, with the majority of patients having undetectable serum levels. Reducing serum opioid concentrations in cancer patients may have implications with respect to restoring bowel function, improving fatigue, and promoting the integrity of antitumor immune function and warrants further study.

Background: The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs., Methods: We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids., Results: Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p<0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p<0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p<0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072., Interpretation: Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation., Funding: Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Nalbuphine has been suggested to be used for post-cesarean section (CS) intravenous analgesia. However, ideal concentration of nalbuphine for such analgesia remains unclear. The present study was conducted to explore an ideal concentration of nalbuphine for post-CS intravenous analgesia by evaluating the analgesic effects and side-effects of three different concentrations of nalbuphine combined with hydromorphone for post-CS intravenous analgesia in healthy parturients., Methods: One-hundred-and-fourteen parturients undergoing elective CS were randomly allocated to one of three groups (38 subjects per group) according to an Excel-generated random number sheet to receive hydromorphone 0.05 mg/mL + nalbuphine 0.5 mg/mL (group LN), hydromorphone 0.05 mg/mL + nalbuphine 0.7 mg/mL (group MN), and hydromorphone 0.05 mg/mL + nalbuphine 0.9 mg/mL (group HN) using patient-controlled analgesia (PCA) pump. Visual analog scale (VAS) for pain, PCA bolus demands, cumulative PCA dose, satisfaction score, Ramsay score, and side-effects such as urinary retention were recorded., Results: The number of PCA bolus demands and cumulative PCA dose during the first 48 h after CS were significantly higher in group LN (21 ± 16 bolus, 129 ± 25 mL) than those in group MN (15 ± 10 bolus, 120 ± 16 mL) (both P < 0.05) and group HN (13 ± 9 bolus, 117 ± 13 mL) (both P < 0.01), but no difference was found between group HN and group MN (both P > 0.05). VAS scores were significantly lower in group HN than those in group MN and group LN for uterine cramping pain at rest and after breast-feeding within 12 h after CS (all P < 0.01) and VAS scores were significantly higher in group LN than those in group MN and group HN when oxytocin was intravenously infused within 3 days after CS (all P < 0.05), whereas VAS scores were not statistically different among groups for incisional pain (all P > 0.05). Ramsay sedation scale score in group HN was significantly higher than that in group MN at 8 and 12 h after CS (all P < 0.01) and group LN at 4, 8, 12, 24 h after CS (all P < 0.05)., Conclusions: Hydromorphone 0.05 mg/mL + nalbuphine 0.7 mg/mL for intravenous PCA could effectively improve the incisional pain and uterine cramping pain management and improve comfort in patients after CS., Trial Registration Number: ChiCTR1800015014, http://www.chictr.org.cn/ Chinese Clinical Trial Registry.

Objectives: Hydromorphone (HM) is a potent μ-opioid receptor agonist with high susceptibility for abuse. A prodrug of hydromorphone, asalhydromorphone (ASAL-HM), has been designed to deter nonoral forms of abuse associated with hydromorphone. This study evaluated the intranasal (IN) pharmacokinetics and exploratory abuse potential of ASAL-HM compared with HM., Design: Single-center, randomized, double-blind, crossover study., Setting: Clinical research site., Subjects: Healthy adult, nondependent recreational opioid users., Methods: Subjects (N = 26) were randomized to receive IN administration of 16.1 mg of ASAL-HM and 8.0 mg of HM (molar-equivalent with respect to hydromorphone). Blood samples were taken through 24 hours postdose, and pharmacodynamic end points (Drug Liking, Feeling High, Take Drug Again, Overall Drug Liking) were assessed through eight hours postdose. Nasal irritation and safety were also assessed., Results: Relative to IN HM, the rate (Cmax) and extent (area under the curve [AUC0-last, AUC0-inf]) of exposure to hydromorphone following IN ASAL-HM were reduced by ≥50%. Consistent with these findings, scores on "at-the-moment" (i.e., Drug Liking Emax, High Emax) and retrospective (i.e., Take Drug Again, Overall Drug Liking) end points were statistically significantly lower for IN ASAL-HM, with mean/median differences ranging from 11.4 to 25.0 points. ASAL-HM produced greater nasal-related effects, such as nasal burning and facial pain, and a lower incidence of typical opioid-related adverse events such as euphoria, pruritus, and somnolence., Conclusions: The novel hydromorphone prodrug ASAL-HM produced marked reductions in hydromorphone exposure and abuse-related effects following IN administration compared with HM. ASAL-HM has desirable molecular features for incorporation into putative abuse-deterrent immediate-release and extended-release hydromorphone products., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To compare the pharmacokinetics and pharmacodynamics of hydromorphone in horses after intravenous (IV) and intramuscular (IM) administration., Study Design: Randomized, masked, crossover design., Animals: A total of six adult horses weighing [mean ± standard deviation (SD))] 447 ± 61 kg., Methods: Horses were administered three treatments with a 7 day washout. Treatments were hydromorphone 0.04 mg kg ⁻1 IV with saline administered IM (H-IV), hydromorphone 0.04 mg kg ⁻1 IM with saline IV (H-IM), or saline IV and IM (P). Blood was collected for hydromorphone plasma concentration at multiple time points for 24 hours after treatments. Pharmacodynamic data were collected for 24 hours after treatments. Variables included thermal nociceptive threshold, heart rate (HR), respiratory frequency (f R ), rectal temperature, and fecal weight. Data were analyzed using mixed-effects linear models. A p value of less than 0.05 was considered statistically significant., Results: The mean ± SD hydromorphone terminal half-life (t 1/2 ), clearance and volume of distribution of H-IV were 19 ± 8 minutes, 79 ± 12.9 mL minute ⁻1 kg ⁻1 and 1125 ± 309 mL kg ⁻1 . The t 1/2 was 26.7 ± 9.25 minutes for H-IM. Area under the curve was 518 ± 87.5 and 1128 ± 810 minute ng mL ⁻1 for H-IV and H-IM, respectively. The IM bioavailability was 217%. The overall thermal thresholds for both H-IV and H-IM were significantly greater than P (p < 0.0001 for both) and baseline (p = 0.006). There was no difference in thermal threshold between H-IV and H-IM. No difference was found in physical examination variables among groups or in comparison to baseline. Fecal weight was significantly less than P for H-IV and H-IM (p = 0.02)., Conclusions and Clinical Relevance: IM hydromorphone has high bioavailability and provides a similar degree of antinociception to IV administration. IM hydromorphone in horses provides a similar degree and duration of antinociception to IV administration., (Published by Elsevier Ltd.)

Competing Interests: Competing interests: Christy Sutherland is the medical director of PHS Community Services Society, a nonprofit that provides housing and harm reduction services. Dr. Sutherland created and implemented the injectable opioid agonist therapy program for PHS Community Services Society. Seonaid Nolan is supported by a Michael Smith Foundation for Health Research Award and the University of British Columbia’s Steven Diamond Professorship in Addiction Care Innovation. No other competing interests were declared.

Objective: To determine the ability to evaluate laryngeal function under sedation with dexmedetomidine alone or in combination with opioids., Study Design: Randomized, crossover, blinded study., Animals: Eight adult research hounds weighing 8 to 22.5 kg., Methods: Dogs were sedated with propofol, dexmedetomidine, dexmedetomidine and butorphanol, or dexmedetomidine and hydromorphone. Digital images were collected with video laryngoscopy before and after doxapram administration. Maximal inspiratory normalized glottal gap (GGA n ) and laryngeal motion were compared between and within protocols before and after doxapram by using a difference of least squares mean., Results: Normal laryngeal function was confirmed in all dogs with all protocols except propofol, which resulted in two false positive results. No difference between protocols was detected for predoxapram GGA n . Postdoxapram GGA n was greater than predoxapram GGA n for all four sedation protocols (P ≤ .0030). Compared with propofol, postdoxapram GGA n was greater for all three dexmedetomidine protocols (P ≤ .0420)., Conclusion: Dexmedetomidine alone or in combination with opioids was an effective sedation protocol for laryngeal examination, producing sufficient immobilization to prevent jaw motion and without affecting arytenoid abduction., Clinical Significance: Dexmedetomidine sedation does not inhibit normal laryngeal motion. Laryngeal examination with propofol alone can produce false positive results., (© 2019 The American College of Veterinary Surgeons.)

Background: Opioids have high abuse potential and pose a major public health concern. Yet, a large percentage of individuals exposed to opioids do not develop problematic use. Individual differences in opioid abuse potential are not well understood., Methods: This within-subject (N = 16), double-blind, double-dummy, human laboratory study evaluated individual differences in response to dose (placebo, low, medium, high) following administration of heroin and hydromorphone through intravenous and subcutaneous routes, in opioid-experienced but non physically-dependent participants. Outcomes were self-reported visual analog scale (VAS) ratings (High, Liking, Drug Effect, Good Effect, Rush), pupil diameter change from baseline, and crossover point on the Drug vs. Money questionnaire. The degree to which results were consistent across measures within an individual was assessed using a mixed-effects model from which an intraclass correlation coefficient measure of between and within-subject variance was derived., Results: The mixed effects model fit was significant (p < 0.0001) and revealed that 85.5% of the explainable variance was due to between-subject effects, suggesting the responses within an individual were highly consistent. Visual inspection reveals a myriad response pattern across participants, with some demonstrating classic dose-effect responses and others not differentiating any active doses from placebo., Conclusions: Data suggest the abuse potential of opioids is significantly different between individuals but that the experience within an individual is highly consistent. Research to prospectively characterize and evaluate mechanisms underlying these differences is warranted and may provide a foundation to help identify persons at heightened risk of transitioning from opioid exposure to misuse and/or opioid use disorder., (Copyright © 2019. Published by Elsevier B.V.)

Objective: To systematically review the literature for studies comparing the efficacy of opioid analgesics for older adults (≥ 65 years) presenting to the emergency department (ED) with acute pain., Data Sources: The Cochrane Library, MEDLINE, EMBASE, Web of Science, and CINAHL were searched up to August or September 2017. Reference lists were searched for potential articles and ClinicalTrials.gov was searched for unpublished trials., Study Selection: Randomized controlled trials (RCTs) were sought that compared the efficacy of 2 or more opioid analgesics for acute pain in older patients (≥ 65 years) in the ED. Two reviewers independently screened abstracts, assessed study quality, and extracted data., Synthesis: After screening titles and abstracts of 1315 citations, the full texts of 63 studies were reviewed and 1 RCT met the inclusion criteria. This study randomized older adult patients presenting to an urban academic ED with acute, severe pain to receive a single dose of either 0.0075 mg/kg intravenous hydromorphone or 0.05 mg/kg intravenous morphine. This study found no clinical or statistical difference between the 2 treatments., Conclusion: The lack of published research in this area demonstrates a considerable gap in knowledge of the comparative efficacy of opioid analgesics in the growing older adult patient population. Physicians are often uncertain in their choice of analgesia, potentially contributing to the undertreatment of pain. It is clear that well designed RCTs are urgently needed., (Copyright© the College of Family Physicians of Canada.)

Objective: To determine which non-narcotic analgesic, acetaminophen (Ofirmev®) or ketorolac (Toradol®), provides better post-operative pain control when combined with an opioid patient-controlled analgesia (PCA) pump. Secondary objectives include comparisons of the rates of ileus, post-operative bleeding, transfusions, and length-of-hospitalization (LOH)., Methods: A prospective, randomized trial of acetaminophen (A) 1-g intravenous (IV) every 6-h or ketorolac (K) 15-mg IV every 6-h from post-operative day 1-3 in addition to an opioid PCA for patients undergoing benign or malignant gynecologic laparotomy procedures was performed. Abstracted data included pain levels via visual analogue pain scales (VAS), amount of narcotic used, hepatic enzyme levels, hemoglobin, urine output, blood transfusions, time to return of flatus and LOH., Results: One-hundred patients were accrued and underwent 55 benign gynecologic laparotomies and 45 cancer-related laparotomies. VAS pain levels (3.3 K, 3.5 A) and morphine PCA use (79.1 oral morphine equivalents [OME] K vs. 84.5 A) were not different, however dilaudid PCA usage was less by K patients (84.4 OME K and 136.8 OME A, p < 0.001). There was a significant hemoglobin change between the two groups (2.6 g K vs. 2 g A, p = 0.015), however blood transfusions were equal (28% K, 22% A, p > 0.05). Return of flatus was 2.7-days for K vs. 3.4-days for A (p = 0.011) and LOH was not different (4.4-days K vs. 5.1-days A, p = 0.094)., Conclusions: Both intravenous ketorolac and acetaminophen provide similar post-operative analgesia through VAS pain scales and total usage of morphine via PCA pumps. Use of ketorolac with dilaudid PCA was associated with less dependence on dilaudid and a quicker return of bowel function than acetaminophen, however length of stay and transfusion rates were not different., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: To compare the pharmacokinetics of fentanyl at lower (LHR) or higher heart rate (HHR) in dogs anesthetized with isoflurane., Study Design: Prospective, randomized, crossover controlled trial., Animals: A group of six healthy 13-month-old male Beagle dogs weighing 9.9 ± 0.7 kg (mean ± standard deviation)., Methods: Dogs were allocated to two treatments: LHR (HR: 45-75 beats minute -1 ) and HHR (HR: 100-130 beats minute -1 ). Anesthesia was maintained with isoflurane and hydromorphone (0.1 mg kg -1 followed by 0.02-0.10 mg kg -1 hour -1 ) for both treatments. Glycopyrrolate was administered in HHR to maintain HR within the desired range. Afterwards, fentanyl (20 μg kg -1 ) was intravenously administered over 5 minutes. Arterial blood samples were collected for plasma fentanyl concentration measurement by liquid chromatography/mass spectrometry. The pharmacokinetics of fentanyl were compared between treatments and the differences were considered significant at p < 0.05., Results: A three-compartment model best fitted the changes in plasma fentanyl concentration. Clearance (CL; mL minute -1 kg -1 ) was 33.2 (24.0-48.0) and 61.3 (44.5-72.7), maximum concentration (ng mL -1 ) 33.6 (23.4-36.6) and 20.0 (16.7-28.0), apparent volume of the rapid peripheral compartment (mL kg -1 ) 436 (352-723) and 925 (499-1887), apparent volume at steady state (mL kg -1 ) 4064 (3453-6546) and 7195 (5077-8601), cardiac index (CI; mL minute -1 m -2 ) 2.83 (1.98-3.67) and 4.91 (3.22-6.09) and HR (beats minute -1 ) 68 (49-72) and 120 (102-129) for LHR and HHR, respectively, with significant differences between treatments. Significant correlations (0.92 and 0.90) were found between CI and CL, and between HR and CL, respectively., Conclusions and Clinical Relevance: The increase in HR and the resultant improvement in cardiac output increased fentanyl CL and volume of distribution, which resulted in a decrease in plasma fentanyl concentration in isoflurane-anesthetized dogs., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: In view of the recent opioid crisis, ways to promote safe and effective opioid-related practices are needed. Faster intravenous (iv) opioid infusion rates can result in increased adverse effects and risk for nonmedical opioid use. Data on best practices regarding safe iv opioid administration for cancer pain are limited. This study examined iv opioid bolus infusion practices and perceptions about opioids in cancer pain among 4 groups of inpatient oncology nurses., Methods: An anonymous cross-sectional survey was conducted among oncology nurses working in medical, surgical, intensive care unit (ICU), and emergency department (ED) settings. An iv opioid bolus infusion speed less than 120 seconds was considered too fast., Results: The participant response rate was 59% (731 of 1234). Approximately 58%, 54%, and 58% of all nurses administered morphine, hydromorphone, and fentanyl, respectively, in less than 120 seconds. The median morphine infusion speeds were 55, 60, 60, and 85 seconds for ICU, surgical, ED, and medical unit nurses, respectively (P = .0002). The odds ratios for infusing too fast were 2.04 and 2.52 for ED (P = .039) and ICU nurses (P = .003), respectively, in comparison with medical unit nurses, and they were 0.27 and 0.18 with frequent (P = .003) and very frequent use of a timing device (P = .0001), respectively, in comparison with no use., Conclusions: More than half the nurses working in the inpatient setting reported administering iv opioids too fast. ICU nurses administered opioids the fastest. Nurses who frequently used a timing device were less likely to infuse too fast. Further research is needed to standardize and improve the safe intermittent administration of iv opioids to patients with cancer., (© 2019 American Cancer Society.)

Background: The differences in post-operative pain are unclear between the primiparas who underwent a primary cesarean section and multiparas who underwent their first repeat cesarean section. The study aimed to explore the possible differences in postoperative pain between primiparas and multiparas., Methods: A prospective cohort study was performed only including women who underwent cesarean deliveries under spinal anesthesia. Postoperative patient-controlled intravenous analgesia (PCIA) was administered to all subjects with 0.2 mg/kg hydromorphone and 4 mg/kg flurbiprofen; the pump was programmed as 2.0 mL/h background infusion with a loading dose of 1 mL and a lockout period of 15 min. Postoperative incision and visceral pain intensity were evaluated using the visual analogue scale, and inadequate analgesia was defined as a visual analogue scale score ≥ 40 during 48 h post-operation. Additionally, the patients' pain statuses in postoperative week 1 and week 4 were also assessed during follow-up via telephone., Results: From January to May 2017, a total of 168 patients (67 primiparas and 101 multiparas) were included. The relative risk for multiparas to experience inadequate analgesia on incision pain was 0.42 (95% CI: 0.25 to 0.74) compared to primiparas. In patients aged < 30 years, inadequate analgesia on visceral pain was higher in multiparas than in primiparas (RR, 3.56 [1.05 to 12.04], P = 0.025). There was no significant difference in the combined incidence of inadequate analgesia in both types of pain between the multiparas and primiparas (33.7% vs. 40.2%, P = 0.381). No difference was found in PCIA use between the two groups (111.1 ± 36.0 mL vs. 110.9 ± 37.3 mL, P = 0.979). In addition, a significantly higher incidence of pain was noted 4 weeks post-surgery in primiparas than that in multiparas (62.2% vs. 37.7%, P = 0.011)., Conclusion: Multiparas who underwent their first repeat cesarean section have a lower for inadequate analgesia on incision pain during the first 48 h after surgery than primiparas. Multiparas aged under 30 years may be more prone to experiencing postoperative inadequate analgesia on visceral pain., Trail Registration: ClinicalTrial.gov: NCT03009955 , Date registered: December 30, 2016.

We present the case of a 51-year-old man with a history of recurrent lung cancer after left upper lobectomy who presented for an elective completion pneumonectomy via a bilateral anterior thoracotomy incision. At the completion of surgery, bilateral multilevel intercostal infiltration was performed with liposomal bupivacaine. Due to poorly controlled postoperative pain after extubation, a thoracic epidural was placed in the intensive care unit. An opioid-only infusion was started and transitioned to a local anesthetic-based infusion on postoperative day 2. This case report represents a novel stepwise approach of thoracic epidural management after surgical infiltration of liposomal bupivacaine.

Competing Interests: Competing interests: Marie-Ève Goyer reports receiving an honorarium and training from Gilead Sciences, outside of the submitted work. Bernard Le Foll reports receiving grants from Pfizer and Brainsway, Bioprojet, Alkermes, Canopy and the American Chemical Society, as well as nonfinancial support from Aurora, outside the submitted work. Josey Ross is employed by the BC Centre on Substance Use, the British Columbia node of the Canadian Research Initiative in Substance Misuse (CRISM). Christy Sutherland is employed by the BC Centre on Substance Use and is also the medical director of PHS Community Services Society, which provides injectable opioid agonist treatment. Michael Trew works for Alberta Health Services; the development of injectable opioid agonist treament clinics in Alberta have been partially funded through specific grants from the Alberta Ministry of Health for this work. Nadia Fairbairn reports receiving personal fees from British Columbia Centre on Substance Use, during the conduct of the study. No other competing interests were declared.

Objectives: The present study aims to describe a 3-day induction protocol for injectable hydromorphone (HDM) and diacetylmorphine (DAM) used in 3 Canadian studies and examine rates of opioid-related overdose and somnolence during this induction phase., Methods: The induction protocol and associated data on opioid-related overdose and somnolence are derived from 2 clinical trials and one cohort study conducted in Vancouver and Montreal (2005-2008; 2011-2014; 2014-2018). In this analysis, using the Medical Dictionary for Regulatory Activities coding system we report somnolence (ie, drowsiness, sleepiness, grogginess) and opioid overdose as adverse events. Overdoses requiring intervention with naloxone are coded as severe adverse events., Results: Data from the 3 studies provides a total of 1175 induction injections days, with 700 induction injection days for DAM, and 475 induction injection days for HDM. There were 34 related somnolence and adverse event (AE) overdoses (4.899 per 100 injection days) in DAM and 6 (1.467 per 100 days) in HDM. Four opioid overdoses requiring naloxone (0.571 per 100 injection days) were registered in DAM and 1 in HDM (0.211 per 100 injection days), all safely mitigated onsite. The first week maximum daily dose patients received were on average 433.62 mg [standard deviation (SD) = 137.92] and 223.26 mg (SD = 68.06) for DAM and HDM, respectively., Conclusions: A 3-day induction protocol allowed patients to safely reach high doses of injectable hydromorphone and diacetylmorphine in a timely manner. These findings suggest that safety is not an evidence-based barrier to the implementation of treatment with injectable hydromorphone and diacetylmorphine.

Opiates play an important role in the control of pain associated with thoracotomy in both people and animals. However, key side effects, including sedation and respiratory depression, could limit the use of opiates in animals that are lethargic due to cardiac disease. In addition, a rare side effect-neuroexcitation resulting in pathologic behavioral changes (seizures, mania, muscle fasciculation)-after the administration of morphine or hydromorphone is well-documented in many species. In pigs, however, these drugs have been shown to stimulate an increase in normal activity. In the case presented, we describe a Yorkshire-cross pig which, after myocardial infarction surgery, went from nonresponsive to alert, responsive, and eating within 30 min of an injection of hydromorphone. This pig was not demonstrating any signs associated with pain at this time, suggesting that the positive response was due to neural stimulation. This case report is the first to describe the use of hydromorphone-a potent, pure μ opiate agonist-for its neurostimulatory effect in pigs with experimentally-induced cardiac disease.

Background: Injection drug use-associated endocarditis (IDUaIE) incidence in Ontario has recently been associated with hydromorphone prescribing rates. Staphylococcus aureus causes the majority of cases of IDUaIE in Ontario and across North America. Hydromorphone controlled-release (Hydromorphone-CR) requires a complex technique for injection and therefore provides multiple opportunities for contamination. Hydromorphone-CR contains several excipients, which could enhance staphylococcal survival and increase risk of contaminating the injectate., Methods: Used injection drug preparation equipment (cookers/filters) was collected from persons who inject drugs (PWID), rinsed with water, and plated on Mannitol salt agar. Bacterial isolates from bacteremic PWID were used to assess the survival of S. aureus and Streptococcus pyogenes on cookers/filters with Hydromorphone-CR, hydromorphone immediate-release (Hydromorphone-IR) or oxycodone controlled-release (Oxycodone-CR). The solutions spiked with S. aureus were heated and the remaining viable bacteria enumerated., Results: S. aureus was detected in 12/87 (14%, 95%CI 8-23%) cookers/filters samples used for injection of Hydromorphone-CR. Hydromorphone-CR was the only opioid associated with greater survival of methicillin-sensitive S. aureus (MSSA) and methicillin-resistant S. aureus (MRSA) on cookers/filters when compared to sterile water vehicle control. There was a ~2 log reduction in the number of S. aureus that survived when cookers/filters were heated., Conclusion: 14% of all cookers/filters used in the preparation of Hydromorphone-CR were contaminated with S. aureus. Hydromorphone-CR prolongs the survival of MRSA and MSSA in cookers/filters. Heating cookers/filters may be a harm-reduction strategy., Competing Interests: The authors have declared that no competing interests exist.

Study Objective: We compare the efficacy and safety of intravenous lidocaine with that of hydromorphone for the treatment of acute abdominal pain in the emergency department (ED)., Methods: This was a randomized, double-blind, clinical trial conducted in 2 EDs in the Bronx, NY. Adults weighing 60 to 120 kg were randomized to receive 120 mg of intravenous lidocaine or 1 mg of intravenous hydromorphone. Thirty minutes after administration of the first dose of the study drug, participants were asked whether they needed a second dose of the investigational medication to which they were randomized. Patients were also stratified according to clinical suspicion of nephrolithiasis. The primary outcome was improvement in pain scores of 0 to 10 between baseline and 90 minutes. An important secondary outcome was need for "off-protocol" parenteral analgesics, including opioids and nonsteroidal anti-inflammatory drugs., Results: We enrolled 154 patients, of whom 77 received lidocaine and 77 received hydromorphone. By 90 minutes, patients randomized to lidocaine improved by a mean of 3.8 points on the 0-to-10 scale, whereas those randomized to hydromorphone improved by a mean of 5.0 points (mean difference 1.2; 95% confidence interval 0.3 to 2.2). Need for off-protocol "rescue" analgesics occurred for 39 of 77 lidocaine patients (51%) and 20 of 77 hydromorphone patients (26%) (difference 25%; 95% confidence interval 10% to 40%). Adverse events were comparable between groups. Among the subset of 22 patients with nephrolithiasis, lidocaine patients reported a mean improvement of 3.4 points on the pain scale, whereas hydromorphone patients reported a mean improvement of 6.4 points (mean difference 3.0; 95% confidence interval 0.5 to 5.5)., Conclusion: Intravenous hydromorphone was superior to intravenous lidocaine both for general abdominal pain and a subset of patients with nephrolithiasis. A majority of patients randomly allocated to lidocaine required additional analgesics., (Copyright © 2019 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy of hydromorphone and dexmedetomidine at inducing emesis in cats., Design: Prospective, blinded, randomized crossover study., Setting: Veterinary university teaching hospital., Animals: 12 healthy purpose-bred cats., Interventions: Cats were randomly assigned to receive hydromorphone (0.1 mg/kg, subcutaneously) or dexmedetomidine (7 μg/kg, IM). Following administration, the incidences of emesis, number of emetic events, signs of nausea (hypersalivation, lip licking), temperature, heart rate, respiratory rate, and sedation score were recorded for 6 hours., Measurements and Main Results: Emesis was successful in 9 of 12 (75%) cats when treated with hydromorphone and in 7 of 12 (58%) cats when treated with dexmedetomidine (P = 0.67). Dexmedetomidine was more likely to cause sedation than hydromorphone (P < 0.001). Heart rate in cats was significantly decreased at 1 and 2 hours post-hydromorphone (P = 0.003, 0.014, respectively) and at 1, 2, 3, 5, 6 hours post-dexmedetomidine (P = 0.001, 0.003, 0.038, 0.013, 0.001, respectively). Cats were more likely to develop an increase in body temperature with hydromorphone administration although this was not clinically significant., Conclusions: Results of the present study indicate that hydromorphone is an effective alternative to dexmedetomidine for the induction of emesis in cats. Hydromorphone appears to cause less sedation and less decrease in heart rate. Further investigation into the most adequate dose of hydromorphone for optimizing emesis is warranted., (© Veterinary Emergency and Critical Care Society 2019.)

Objective: To evaluate thermal antinociception from intravenous (IV) administration of hydromorphone alone or followed by butorphanol or naloxone in cats., Study Design: Randomized, controlled, masked, crossover design., Animals: A group of eight adult female cats., Methods: Cats were administered six treatments of two IV injections 30 minutes apart: treatments S-S, two 0.9% saline; H-S, hydromorphone (0.1 mg kg -1 ) and saline; H-LB, hydromorphone and butorphanol (0.02 mg kg -1 ); H-MB, hydromorphone and butorphanol (0.1 mg kg -1 ); H-HB, hydromorphone and butorphanol (0.2 mg kg -1 ); H-N, hydromorphone and naloxone (0.04 mg kg -1 ). Skin temperature (ST), thermal threshold (TT) and sedation score (SS) were recorded before (baseline) and for 8 hours after the first injection. Percentage maximum possible effect (%MPE), thermal excursion (TE), TT, SS and ST were compared using two-way repeated measures anova or Friedman test followed by Tukey's or Dunn's multiple comparisons test when appropriate. Significance was set at p ≤ 0.05., Results: Data from seven cats were analyzed. There were no significant differences among treatments in baseline values, SS and within S-S over time. Compared with respective 0.5 hour values following hydromorphone administration, %MPE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 4-8 hours for H-MB; at 6-8 hours for H-HB and at 1-8 hours for H-N. Compared with respective 0.5 hour values, TE was significantly lower at 4-8 hours for H-S; at 3-8 hours for H-LB; at 2 and 4-8 hours for H-MB; at 6 and 8 hours for H-HB and at 1-8 hours for H-N., Conclusions and Clinical Relevance: Butorphanol and naloxone reduced hydromorphone-induced thermal antinociception. Butorphanol preserved hydromorphone antinociceptive properties better than naloxone. Butorphanol is recommended during non-life-threatening scenarios as a partial reversal agent for hydromorphone in cats., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: In a double-blind, non-inferiority randomized controlled trial injectable hydromorphone, a licensed short acting opioid analgesic, was shown to be as effective as diacetylmorphine for the treatment of severe opioid use disorder. An appropriate question is whether hydromorphone offered open-label can attract and retain patients., Methods: This is a retrospective study, using daily prescription data from the Crosstown Clinic in Vancouver, Canada. Treatment retention among participants who had the opportunity to receive open-label injectable hydromorphone for at least 90 consecutive days (n = 108) before having the choice of receiving open-label diacetylmorphine, was compared to their retention outcomes with double-blind injectable opioid agonist treatment (iOAT). McNemar tests analyzed differences in proportions; a conditional logistic model estimated exact odds ratios; Pairwise t-tests analyzed differences in total number of treatment days; and Kaplan-Meier curves and clustered log-rank tests compared time to first 30 continuous days without injectable treatment., Results: A total of 74 participants (68.5%) were retained in both open-label hydromorphone and double-blind iOAT. Open-label hydromorphone was not significantly associated with lower retention (OR = 0.5; 95% CI: 0.2, 1.1; p = .10). Participants attended a mean of 84.4 (SD = 15.8) days of iOAT in the trial and 80.5 (SD = 22.0) days in open-label hydromorphone (mean difference of -3.9; 95% CI = -8.9, 1.1). Kaplan-Meier curves and log-rank tests were not statistically significant., Conclusion: As treatment with injectable hydromorphone expands across Canada, our study contributes in a unique manner by providing evidence that the high retention rates observed during the clinical trial were maintained when participants started open-label hydromorphone., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objectives: We aimed to describe the analgesic efficacy, duration of analgesia, and adverse event profile associated with intranasal hydromorphone in children with acute pain presenting to an emergency department., Methods: Prospective dose titration pilot study of otherwise healthy children 4 to 17-years-old with moderate to severe pain who required a parenteral opioid. All patients received an initial intranasal hydromorophone dose of 0.03 mg/kg. The need for additional analgesia was assessed at 15 and 30 min; an additional 0.015 mg/kg was given at each assessment, if required. Need for rescue analgesic, pain intensity and adverse events were assessed until 6 h after hydromorphone administration or until patients were discharged, underwent a procedure to treat their painful condition, or received a rescue analgesic., Results: We enrolled 35 children. Fifteen, 11, and 9 children required a total dose of 0.03, 0.045, and 0.06 mg/kg, respectively. Patients in each dose group experienced an absolute decrease in pain score of ≥3/10 and percent reduction >40% within 5-15 min of completing dose-titration administration of hydromorphone. Duration of analgesia (i.e. time until rescue analgesic administered) >1 h was observed in 85.7% of patients. Patients not requiring rescue analgesics had mild or no pain until discharged or their painful conditions were treated. Three (8.6%) patients required a rescue analgesic <1 h after hydromorphone administration. There were no major adverse events., Conclusions: Intranasal hydromorphone led to rapid, clinically significant and frequently sustained decreases in pain intensity in children. No major adverse events were observed in this preliminary sample. Clinical Trials Registration Number: NCT02437669., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A 72-year-old woman with suicidal ideations for the first time was seen for a follow-up medical visit. Patient diagnosed with bipolar disorder II, chronic complex pain and other complex medical issues. Patient was on long-standing chronic opioid agonist therapy. Patient was prescribed oral hydromorphone to supplement her chronic opioid regimen. Within 24 hours, the patient reported no further suicidal ideations and there were no reported complications. The case provides impetus for further study as to what interventions work best for patients who present with acute suicidal ideations. The case acknowledges cultural issues and implicit biases that can influence medical care and perceptions thereof. Implicit biases may be particularly apparent as they relate to mental health concerns and the use of substances that are susceptible to abuse. The most important clinical lesson reminder may be the importance of adequate documentation and discussion be provided when one prescribes an opioid in a novel way in a special clinical context., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Describe the pharmacokinetics and pharmacodynamics of intravenous hydromorphone in healthy horses., Study Design: Masked, randomized, cross-over, Latin square design., Animals: A group of eight healthy adult horses METHODS: Horses were administered each of four treatments with an 8 day washout. Treatments groups included intravenous hydromorphone 0.02 mg kg -1 (LD), 0.04 mg kg -1 (MD), 0.08 mg kg -1 (HD) and saline (P). Blood samples for hydromorphone analysis were obtained for 24 hours after treatment. Plasma hydromorphone was quantified and pharmacokinetic parameters were determined using non-compartmental analysis. Pharmacodynamic data collected for 24 hours after treatment included thermal nociceptive threshold, heart rate (HR), respiratory rate (f R ) and rectal temperature, and analyzed using mixed-effects linear models., Results: Mean (± standard deviation) hydromorphone terminal half-life (t 1/2 ), systemic clearance and apparent volume of distribution at steady state (Vd ss ) were 18.1 ± 18.6, 34.0 ± 12.8, and 41.3 ± 32.5 minutes, 66.6 ± 5.3, 550.0 ± 76.4, and 92.7 ± 13.9 mL kg -1 minute -1 , and 1118 ± 369, 1460 ± 325 and 2242 ± 950 mL kg -1 for treatments LD, MD and HD, respectively. Thermal threshold increased significantly compared to baseline for all treatments for up to 12 hours. HR was elevated above baseline in treatments LD, MD and HD, extending to 30, 15 and 105 minutes after treatment, respectively. Respiratory rate was elevated above baseline in treatments MD and HD from 30 to 195 minutes and from 45 to 480 minutes after treatment, respectively. Temperature was elevated above baseline in treatment HD until 255 minutes after treatment., Conclusions: Hydromorphone exhibited a short t 1/2 , rapid clearance and large Vd ss in horses. It also provided a dose-dependent increase in thermal threshold with associated increases in HR, f R and rectal temperature., Clinical Relevance: Hydromorphone 0.04 mg kg -1 provided clinically relevant thermal antinociception with minimal adverse effects., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Transverse abdominis plane (TAP) block is considered an effective alternative to neuraxial analgesia for abdominal surgery. However, limited evidence supports its use over traditional analgesic modalities in colorectal surgery. This study compared the analgesic efficacy of liposomal bupivacaine TAP block with intrathecal (IT) opioid administration in a multicentre RCT., Methods: Patients undergoing elective small bowel or colorectal resection were randomized to receive TAP block or a single injection of IT analgesia with hydromorphone. Patients were assessed at 4, 8, 16, 24 and 48 h after surgery. Primary outcomes were mean pain scores and morphine milligram equivalents (MMEs) administered within 48 h after surgery. Secondary outcomes included duration of hospital stay, incidence of postoperative ileus and use of intravenous patient-controlled analgesia., Results: In total, 209 patients were recruited and 200 completed the trial (TAP 102, IT 98). The TAP group had a 1·6-point greater mean pain score than the IT group at 4 h after surgery, and this difference lasted for 16 h after operation. The TAP group received more MMEs within the first 24 h after surgery than the IT group (median difference in MMEs 10·0, 95 per cent c.i. 3·0 to 20·5). There were no differences in MME use at 24 and 48 h, or with respect to secondary outcomes., Conclusion: IT opioid administration provided better immediate postoperative pain control than TAP block. Both modalities resulted in low pain scores in patients undergoing elective colorectal surgery and should be considered in multimodal postoperative analgesic plans. Registration number: NCT02356198 ( http://www.clinicaltrials.gov)., (© 2019 BJS Society Ltd Published by John Wiley & Sons Ltd.)

Introduction: A common belief is that some narcotic medications have a higher association with prolonged use. We assessed whether the initial opiate type prescribed to postoperative, opiate-naive orthopaedic trauma patients was associated with prolonged opioid use., Methods: We studied 17,961 adult, opiate-naive patients treated for a surgical musculoskeletal injury. Discharge prescription in morphine milligram equivalents (MMEs, a standardized dosing unit that allows for comparison across opioid types) was calculated. Opioid prescribing beyond 90 days after injury was defined as prolonged use., Results: Initial analysis demonstrated a higher likelihood of prolonged use for patients discharged on hydromorphone or morphine versus hydrocodone. However, when we adjusted for discharge MME, only opioid quantity was predictive of prolonged use (P < 0.001). In addition, discharge MME was associated with opioid type (P < 0.01)., Discussion: Persistent opiate use was associated with discharge opioid quantity, not the opioid type. These results highlight the importance of calculating equivalence doses when selecting opioid types and considering amount of narcotics prescribed., Level of Evidence: Level III.

Objective: To determine pharmacokinetic dosing strategy in bearded dragons (Pogona vitticeps) and red-eared sliders (Trachemys scripta elegans) based on two subcutaneously (SC) administered doses of hydromorphone (0.5 and 1.0 mg kg -1 )., Study Design: Randomized crossover study., Animals: Six healthy adult bearded dragons, seven healthy adult red-eared slider turtles., Methods: Hydromorphone (0.5 and 1.0 mg kg -1 ; 2 mg mL -1 ) was administered SC dorsolateral to the scapulae in the bearded dragons and between the head and thoracic limb of the red-eared slider turtles. Blood was collected for hydromorphone plasma concentration analysis from the ventral tail vein in bearded dragons and subcarapacial sinus in turtles before (time 0) hydromorphone administration and at 0.5, 1, 6, 12 and 24 hours., Results: The half-life of hydromorphone administered at 0.5 and 1.0 mg kg -1 was 2.54 and 3.05 hours in bearded dragons and 2.67 and 2.01 hours in red-eared sliders, respectively. The maximum plasma concentrations for 0.5 and 1.0 mg kg -1 were 142 and 369 ng mL -1 in bearded dragons and 1610 and 5142 ng mL -1 in red-eared sliders, respectively. Peak plasma concentrations were detected at 30 minutes for both species. Hydromorphone administered at both dosages provided plasma concentrations of 13-14 ng mL -1 for at least 24 hours in bearded dragons and of 5-6 ng mL -1 for at least 12 hours in red-eared sliders. Clinical sedation was observed for up to 1 hour posthydromorphone (1.0 mg kg -1 ) administration for five of six bearded dragons characterized by low body carriage and decreased response to stimuli. No evidence of clinical sedation was observed in red-eared sliders at either dose., Conclusions and Clinical Relevance: Recommended dosing strategy for hydromorphone is 0.5 mg kg -1 administered SC every 24 hours in bearded dragons and every 12-24 hours in red-eared sliders., (Copyright © 2019 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Background: Approximately 50 million US patients undergo ambulatory surgery annually. Postoperative opioid overprescribing is problematic, yet many patients report inadequate pain relief. In major inpatient surgery, intraoperative single-dose methadone produces better analgesia and reduces opioid use compared with conventional repeated dosing of short-duration opioids. This investigation tested the hypothesis that in same-day ambulatory surgery, intraoperative methadone, compared with short-duration opioids, reduces opioid consumption and pain, and determined an effective intraoperative induction dose of methadone for same-day ambulatory surgery., Methods: A double-blind, dose-escalation protocol randomized 60 patients (2:1) to intraoperative single-dose intravenous methadone (initially 0.1 then 0.15 mg/kg ideal body weight) or conventional as-needed dosing of short-duration opioids (eg, fentanyl, hydromorphone; controls). Intraoperative and postoperative opioid consumption, pain, and opioid side effects were assessed before discharge. Patient home diaries recorded pain, opioid use, and opioid side effects daily for 30 days postoperatively. Primary outcome was in-hospital (intraoperative and postoperative) opioid use. Secondary outcomes were 30 days opioid consumption, pain intensity, and opioid side effects., Results: Median (interquartile range) methadone doses were 6 (5-6) and 9 (8-9) mg in the 0.1 and 0.15 mg/kg methadone groups, respectively. Total opioid consumption (morphine equivalents) in the postanesthesia care unit was significantly less compared with controls (9.3 mg, 1.3-11.0) in subjects receiving 0.15 mg/kg methadone (0.1 mg, 0.1-3.3; P < .001) but not 0.1 mg/kg methadone (5.0 mg, 3.3-8.1; P = .60). Dose-escalation ended at 0.15 mg/kg methadone. Total in-hospital nonmethadone opioid use after short-duration opioid, 0.1 mg/kg methadone, and 0.15 mg/kg methadone was 35.3 (25.0-44.0), 7.1 (3.7-10.0), and 3.3 (0.1-5.8) mg morphine equivalents, respectively (P < .001 for both versus control). In-hospital pain scores and side effects were not different between groups. In the 30 days after discharge, patients who received methadone 0.15 mg/kg had less pain at rest (P = .02) and used fewer opioid pills than controls (P < .0001), whereas patients who received 0.1 mg/kg had no difference in pain at rest (P = .69) and opioid use compared to controls (P = .08)., Conclusions: In same-day discharge surgery, this pilot study identified a single intraoperative dose of methadone (0.15 mg/kg ideal body weight), which decreased intraoperative and postoperative opioid requirements and postoperative pain, compared with conventional intermittent short-duration opioids, with similar side effects.

Objectives: Older adults are at risk for undertreatment of pain. We examined intravenous (IV) acetaminophen as an analgesic adjunct to IV opioids in the care of older emergency department (ED) patients with acute severe pain., Methods: This was a randomized clinical trial conducted in two EDs in the Bronx, New York. Eligible adults aged 65 years and older with acute severe pain were randomized to 0.5 mg of IV hydromorphone and 1 g of IV acetaminophen or 0.5 mg of IV hydromorphone and 100 mL of normal saline placebo. The primary outcome was the between group difference in improvement of numerical rating scale (NRS) pain scores at 60 minutes. Secondary outcomes were the between-group differences in the proportion of patients who chose to forgo additional pain medications at 60 minutes; the proportion who developed side effects; the proportion who required rescue analgesia; and between-group differences in NRS pain scores at 5, 15, 30, and 45 minutes., Results: Eighty-one patients were allocated to each arm. Eighty patients in the IV acetaminophen arm and 79 patients in the placebo arm had sufficient data for analysis. At 60 minutes, patients in the hydromorphone + IV acetaminophen group improved by 5.7 NRS units while those in the hydromorphone + placebo group improved by 5.2 NRS units, for a difference of 0.6 NRS units (95% confidence interval [CI] = -0.4 to 1.5). A total of 28.7% of patients in the hydromorphone + IV acetaminophen group wanted more analgesia at 60 minutes versus 29.1% in the hydromorphone + placebo group, for a difference of -0.4% (95% CI = -14.3% to 13.5%). These differences were neither clinically nor statistically significant. Safety profiles were similar in both groups., Conclusion: In this randomized clinical trial, the addition of IV acetaminophen to IV hydromorphone as an adjunctive analgesic for acute, severe, pain in older adults provided neither clinically nor statistically superior pain relief when compared to hydromorphone alone within the first hour of treatment., (© 2018 by the Society for Academic Emergency Medicine.)

Introduction: Postoperative pain remains the most common challenge following inpatient and outpatient surgeries, and, therefore, opioid analgesics are widely used during the perioperative period. The aim of this study is to examine the efficiency of transversus abdominis plane (TAP) block using liposomal bupivacaine in reducing the use of opioid analgesics during the perioperative period of bariatric procedures., Material and Methods: A retrospective chart review was performed on 191 patients who underwent a laparoscopic bariatric procedure between September 13, 2017, and February 26, 2018. A total of 97 patients received TAP block with liposomal bupivacaine, and 94 patients did not receive TAP block., Results: Baseline patient characteristics were comparable between the two groups. The mean age was 43.7 and 41.1 years, and the mean preoperative body mass index (BMI) was 45.6 and 46.1 kg/m 2 in TAP and non-TAP groups, respectively. In the TAP group, 65 patients (69.2%) received intravenous (IV) hydromorphone or morphine while 93 (95.9%) did in the non-TAP group (p < 0.0001). In the TAP group, 44 (46.8%) received oral opioid analgesic while 73 (75.3%) did in the non-TAP group (p < 0.0001). The odds of receiving IV hydromorphone or morphine for TAP group was about 0.10 times the corresponding odds for non-TAP group, and the odds of receiving oral opioid analgesic for the TAP group was about 0.29 times the corresponding odds for the non-TAP group., Conclusion: The use of preoperative TAP block with liposomal bupivacaine significantly decreased the use of IV and oral opioid analgesics. A larger prospective study may be needed to further validate the results.

Purpose: Single dose of epidural hydromorphone has been introduced to serve as an alternative method for postcesarean section analgesia. However, optimal dose of epidural hydromorphone remains unknown. Hence, we evaluated and compared the analgesic and adverse effects of postoperative different doses of epidural hydromorphone coadministered with ropivacaine after cesarean section., Methods: Eighty term parturients with elective cesarean section under epidural anesthesia were allocated into four groups. Epidural analgesia was administered with an epidural bolus of either 0 mg (group H0), or 0.2 mg (group H1), or 0.4 mg (group H2), or 0.6 mg (group H3) hydromorphone coadministered with ropivacaine. The primary outcome was the visual analogue pain scores (VAPSs) and rescue opioid consumption (PCIA with sulfentanil) in 24 hours. Adverse effects such as respiratory depression, pruritus, nausea, and vomiting were recorded., Results: The VAPSs of group H1 at 2, 4, 6, 12 h and 24 h after surgery was similar to group H0. The VAPSs of group H2 at 4 and 6 h postoperatively were significantly decreased when compared to group H0. But, the VAPSs of group H2 at 2, 12, and 24 h postoperatively were similar to those of group H0. The VAPSs of group H3 at 4, 6, 12 h, and 24 h after surgery were significantly decreased when compared to those of group H0. The total sulfentanil consumption in 24 hours was 90 ± 26  μ g in group H0, 75 ± 29  μ g in group H1, 54 ± 32  μ g in group H2, and 15 ± 16  μ g in group H0. Adverse effects were comparable in the four groups., Conclusions: Epidural administration of 0.6 mg hydromorphone coadministered with ropivacaine after cesarean section provided satisfactory pain relief with less sulfentanil consumption. This trial is registered with ChiCTR-IPR-16010026.

Objectives: Pediatric pain management has rapidly changed over the last 2 decades. In this study, we describe the changing practices and adverse events (AEs) related to patient-controlled analgesia (PCA) and/or nurse-controlled analgesia (NCA) over a 22-year period., Methods: After institutional review board approval, retrospective data from a single tertiary-care pediatric hospital were collected between 1994 and 2016. Subgroup analyses were done for surgical and medical case patients. We reported the number of times that PCA and/or NCA was ordered annually, the median and interquartile ranges for age, PCA and/or NCA duration and length of stay, and AE frequencies., Results: Over 22 years, 32 338 PCAs and/or NCAs were ordered in this institution. Morphine and hydromorphone were used most commonly. Between 1994 and 2006, initial orders for PCA and/or NCA increased 2.5-fold. After 2007, initial orders for PCA and/or NCA rapidly decreased; after 2013, the decrease continued at a slower rate, with a total of 1007 orders in 2016. This decrease occurred despite increased hospital admissions and surgeries. Between 2007 and 2012, peripheral nerve blocks rapidly increased (10-fold). After 2002, 146 AEs were reported (1.0%). Of those, 50.5% were nonintercepted, and 20.6% were intercepted AEs; 5.5% and 6.2% were preventable and nonpreventable AEs, respectively., Conclusions: PCA and/or NCA usage continues to be common in pediatric patients, although usage has declined and stabilized in the setting of other emerging methods of analgesia and increases in the number of minimally invasive surgical procedures. The overall rate of AEs was extremely low. However, improvements to eliminate all errors are needed, especially with medications with a great risk of harm (such as opioids)., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2019 by the American Academy of Pediatrics.)

Study Objective: As clinicians look to nonnarcotic analgesics in the emergency department (ED), it is essential to understand the effectiveness and adverse effects of nonopioid medications in comparison with existing opioid treatments. Studies of intravenous acetaminophen for acute pain in the ED demonstrate mixed results and suffer from small sample sizes and methodological limitations. This study compares intravenous hydromorphone with intravenous acetaminophen in adult ED patients presenting with acute pain., Methods: This was a prospective, randomized, clinical trial comparing 1 g intravenous acetaminophen with 1 mg intravenous hydromorphone for treatment of adults with severe, acute pain in the ED. The primary outcome was between-group difference in change in numeric rating scale from baseline to 60 minutes postadministration of study medication. Secondary outcomes included the difference in proportion of patients in each group who declined additional analgesia at 60 minutes, received additional medication before 60 minutes, and developed nausea, vomiting, or pruritus., Results: Of 220 subjects randomized, 103 patients in each arm had sufficient data for analysis. At 60 minutes, the mean decrease in numeric rating scale pain score was 5.3 in the hydromorphone arm and 3.3 in the acetaminophen arm, a difference of 2.0 (95% confidence interval [CI] 1.2 to 2.7) favoring hydromorphone. A greater proportion of patients in the hydromorphone arm also declined additional analgesia at 60 minutes (65% versus 44%; difference 21%; (95% CI 8% to 35%). There was no difference in the proportion of patients receiving rescue analgesia before 60 minutes. Significantly more subjects in the hydromorphone group developed nausea (19% versus 3%; difference 16%; 95% CI 4% to 28%) and vomiting (14% versus 3%; difference 11%; 95% CI 0% to 23%)., Conclusion: Although both 1 mg intravenous hydromorphone and 1 g intravenous acetaminophen provided clinically meaningful reductions in pain scores, treatment with hydromorphone provided both clinically and statistically greater analgesia than acetaminophen, at the cost of a higher incidence of nausea and vomiting., (Copyright © 2018 American College of Emergency Physicians. Published by Elsevier Inc. All rights reserved.)

Chronic cancer pain remains prevalent and severe for many patients, particularly in those with advanced disease. The effectiveness of analgesic/adjuvant drug treatments in routine practice has changed little in the last 30 years. To address these issues herein, we have developed sustained-release poly(lactic-co-glycolic acid) microparticles of hydromorphone for intrathecal injection aimed at producing prolonged periods of satisfactory analgesia in patients, as a novel strategy for alleviation of intractable cancer-related pain. These hydromorphone-loaded microparticles were produced successfully using organic solvent-free supercritical fluid polymer encapsulation. Drug loading at 9.2% and encapsulation efficacy at 92% were achieved for particles in the desired size range (20-45 μm) with sustained release over a 5-week period in vitro., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the analgesic effects of patient-controlled intravenous analgesia (PCA) with hydromorphone and sufentanil after thoracic surgery on postoperative pulmonary complications (PPCs)., Methods: A total of 142 patients who were scheduled for thoracic surgery were randomly allocated to receive PCA with hydromorphone (group A: experimental group): hydromorphone 0.2 mg/kg + dezocine 0.5 mg/kg + ramosetron 0.6 mg diluted with normal saline to 200 mL; or with sufentanil (group B: control group): sufentanil 3.0μg/kg + dezocine 0.5 mg/kg + ramosetron 0.6 mg diluted with normal saline to 200 mL. The parameters of intravenous analgesia pump were set as background dose 4 ml/h, PCA dose 1 mL, locking time 15 min. Pain NRS (numerical rating scale), Ramsay sedation score, nausea or vomiting score were evaluated at 0 h, 6 h, 12 h, 24 h, 48 h after operation. The cases of PPCs (atelectasis, pulmonary infection, respiratory failure), CRP (C-reaction protein) and inflammatory cells (white cell count and percentage of neutrophils) and blood gas analysis at 12 h after operation, length of ICU and postoperative stay were recorded for each patient., Results: Data of 136 patients were analyzed. Compared with group B (4[IQR:2,2]), the pain NRS in group A (2[IQR:4,4]) was significantly lower at 6 h after operation (P = 0.000). The CRP in group A (69.79 ± 32.13 mg/L) were lower than group B (76.76 ± 43.42 mg/L) after operation, but the difference was not significant (P = 0.427). No difference of nausea or vomiting was found between group A (7.3%) and group B (5.8%) postoperatively (P = 0.999). The PPCs were happened in 11 patients in group A (16.2%) and 22 patients in group B (32.4%) and the difference between two groups was significant (P = 0.027). Seven patients in group A (10.3%) and eighteen patients in group B (26.5%) had clinical evidence of pneumonia and the difference between two groups was significant (P = 0.014). The length of ICU and postoperative stay in group A were 2.73 h and 1.82 days less than group B respectively but the differences were not significant (P = 0.234, P = 0.186 respectively)., Conclusion: Compared with sufentanil, hydromorphone may provide better postoperative analgesic effect with less pulmonary complications for patients undergoing thoracic surgery, and it may accelerate patients' rehabilitation., Trial Registration: Randomized Controlled Trials ChiCTR1800014282c . Registered 3 January 2018.

Hydromorphone has been shown to play protective effect in rat glial cell. However, whether hydromorphone plays important roles in ischemia-reperfusion (IR) injury and the involved signaling pathway remains unclear. In this study, we detected whether HM plays protective effect in IR injury mouse model, further followed by the mechanism exploration. Preconditioning with hydromorphone was performed for continuous 4 days at the doe of 2 mg/kg before IR injury induction. Intraperitoneal injection of rapamycin (Rapa) was administrated to examine the role of mTOR in IR injury. The mRNA expression level was detected by RT-PCR, and protein expression level was detected by western blot. Latency time and apoptosis of hippocampal CA1 neurons were detected 72 h after IR injury induction. Preconditioning with hydromorphone significantly increased Latency time, decreased apoptosis of hippocampal CA1 neurons and suppressed IR induced oxidative stress. Mechanically, preconditioning with hydromorphone increased Bcl-2 and p-mTOR expression levels and decreased Bax expression levels. Rapa administration reverses the role of hydromorphone in protecting hippocampal CA1 neurons from IR injury. Hydromorphone protect hippocampal CA1 neurons from IR injury via activating mTOR signaling pathway., (Copyright © 2018 Elsevier B.V. All rights reserved.)

This paper reviewed the 2002 guidelines established by the National Federation of Cancer Centres. A group of experts nominated by the 3 French Societies involved in the treatment of cancer pain (AFSOS, SFAP, SFETD), established new guidelines ratios for morphine switching and/or changing of route of administration, in patients for whom either pain was not adequatly managed or adverse effects were unbearable. After a rapid reminder of the pharmacokinetics and metabolism properties of morphine, experts explained why the theory of opioid rotation (oxycodone, hydromorphone, fentanyl, methadone, tapentadol) using fixed equianalgesic ratios is not any more appropriate for a secure clinical practice. In the light of recent publications enhancing our knowledge on the efficacy of new drug switching ratios and for changing the route of administration of morphine, the group of experts recommended to use reconsidered switching ratios favoring security upon efficacy, to minimize overdosing and adverse effects. Consequently, after the new conversion ratio (using slow release opioids) was applied, a second titration should be done by means of normal release rescue formulations for breakthrough pain episodes. A smartphone App. OpioConvert ® will be available for rapid and secure dose conversions., (Copyright © 2018 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Sustained release liposomal bupivacaine (LB) is a new pain control option that can reduce opioid use after laparotomy, which is known to prolong ileus, length of stay., Methods: Sixty-one consecutive patients undergoing laparotomy were treated with a standardized multi-modal therapy (MMT) consisting of IV tylenol, toradol, and morphine/dilaudid PCA. Thirty-one of those patients were additionally treated with LB infiltrated during fascial closure. Endpoints were opioid use, time to flatus, length of stay, and complications., Results: Overall opioid use for 72 h was 78 mg of morphine for the MMT + LB group and 112 mg in the MMT control group (p = 0.04). During 0-24 h s PCA use was similar. However, during 24-48 h PCA use was decreased by 46% in the MMT + LB group (p = 0.038), and decreased by 55% during the 48-72 h period (p = 0.019). Time to flatus was decreased by 1.0 days in the MMT + LB group (p = 0.005)., Conclusion: Use of LB in laparotomy patients decreases opioid use, time to flatus, and should be considered as a component of post-operative pain control., (Copyright © 2018 IJS Publishing Group Ltd. Published by Elsevier Ltd. All rights reserved.)

Objectives: Opioids and benzodiazepines are commonly used to provide analgesia and sedation for critically ill children with cardiac disease. These medications have been associated with adverse effects including delirium, dependence, withdrawal, bowel dysfunction, and potential neurodevelopmental abnormalities. Our objective was to implement a risk-stratified opioid and benzodiazepine weaning protocol to reduce the exposure to opioids and benzodiazepines in pediatric patients with cardiac disease., Design: A prospective pre- and postinterventional study., Patients: Critically ill patients less than or equal to 21 years old with acquired or congenital cardiac disease exposed to greater than or equal to 7 days of scheduled opioids ± scheduled benzodiazepines between January 2013 and February 2015., Setting: A 24-bed pediatric cardiac ICU and 21-bed cardiovascular acute ward of an urban stand-alone children's hospital., Intervention: We implemented an evidence-based opioid and benzodiazepine weaning protocol using educational and quality improvement methodology., Measurements and Main Results: One-hundred nineteen critically ill children met the inclusion criteria (64 post intervention, 55 pre intervention). Demographics and risk factors did not differ between groups. Patients in the postintervention period had shorter duration of opioids (19.0 vs 30.0 d; p < 0.01) and duration of benzodiazepines (5.3 vs 22.7 d; p < 0.01). Despite the shorter duration of wean, there was a decrease in withdrawal occurrence (% Withdrawal Assessment Tool score ≥ 4, 4.9% vs 14.1%; p < 0.01). There was an 8-day reduction in hospital length of stay (34 vs 42 d; p < 0.01). There was a decrease in clonidine use (14% vs 32%; p = 0.02) and no change in dexmedetomidine exposure (59% vs 75%; p = 0.08) in the postintervention period., Conclusions: We implemented a risk-stratified opioid and benzodiazepine weaning protocol for critically ill cardiac children that resulted in reduction in opioid and benzodiazepine duration and dose exposure, a decrease in symptoms of withdrawal, and a reduction in hospital length of stay.

Background: With the increasing occurrence of drug shortages, understanding the pharmacokinetics of alternative intrathecal opioid administration has gained importance. In particular, additional data are needed to comprehensively evaluate the analgesic properties of intrathecal hydromorphone in the laboring patient. In a phase 2 clinical trial, we set out to determine the median effective dose (ED 50 ) and time to effectiveness for this drug in this population., Methods: Using Dixon's up-and-down sequential allocation method, twenty women presenting for labor analgesia were prospectively enrolled. A combined spinal-epidural technique was used to deliver the determined dose of intrathecal hydromorphone. Visual analog pain scores were obtained assessing peak pain scores during serial uterine contractions. Effective pain relief was defined as achieving a pain score of less than or equal to 3 out of 10. The dose was deemed to be ineffective if the patient failed to achieve this level of relief after 30 min., Results: The ED 50 of hydromorphone in our population was 10.9 μg (95% confidence interval 5.6-16.2 μg). Amongst patients for whom the dose was effective, the median time to pain relief was 24 min. One patient experienced both nausea and pruritus. No other complications were noted., Conclusion: Due to the prolonged time to onset, hydromorphone cannot be recommended in favor of substantively better alternatives such as sufentanil and fentanyl., Trial Registration: Clinicaltrials.gov registration number: NCT01598506.

Objectives: Intrathecal (IT) trial is a prognostic interventional pain management procedure employed to determine the potential success of treating intractable pain with an implantable infusion device system. There is a dearth of data regarding trials with continuous infusion of combination therapy (e.g. opioid combined with local anesthetic). The objective of the this study was to determine the overall outcomes of continuous infusion IT trials and factors influencing long-term success of IT therapy in patients with chronic intractable pain post-laminectomy., Materials and Methods: This is a retrospective analysis of all patients with lumbar failed back surgery syndrome (FBSS) who were trialed with a combination of hydromorphone and bupivacaine with a temporary externalized IT catheter from March 2007 to June 2014., Results: From a cohort of 62 patients fulfilling the inclusion criteria, 54 (87.10%) patients had successful IT trials. No significant differences were found between successful and failed trial patients with regards to age, sex, pre-trial pain numeric rating scale scores, pre-trial morphine equivalent daily dose, or trial dosages. Significant positive correlations were found between pretrial oral opioid intake and end of trial hydromorphone dose and hydromorphone dose escalation at 12 months and 24 months., Conclusions: Patients with refractory low back pain due to FBSS who underwent successful combination IT trial with hydromorphone and bupivacaine infused through a temporary IT catheter had significantly improved pain intensity scores following permanent implant. Higher pre-trial MEDD was correlated with higher trial and post-implant opioid doses and higher rates of opioid dose escalation post-implant., (© 2017 International Neuromodulation Society.)

Objective: To observe the effects of hydromorphone and morphine intravenous analgesia on plasma motilin and postoperative nausea and vomiting in patients undergoing a total hysterectomy., Patients and Methods: 80 patients who underwent hysterectomy from April 2015 to June 2016 were randomly divided into two groups, with 40 patients in each group. The two groups received an intravenous infusion of hydromorphone or morphine for analgesia. The VAS pain score and Ramsey sedation score were recorded 4, 8, 12, 24, and 48 hours after the first dose of analgesia. The scores of nausea and vomiting were recorded. The levels of motilin were determined by radioimmunoassay before anesthesia, after anesthesia, during hysterectomy and 1 day after the operation. The results showed that the analgesic effect of hydromorphone was more rapid than morphine., Results: There were significant differences in VAS scores between the two groups at each time point (p<0.05), indicating that the analgesic effect of hydromorphone was better than morphine's one. The scores of Ramsay sedation were less than 6 points at each time point within 48 hours after the operation. The content of plasma motilin in the hydromorphone group was higher than that in the morphine group during the first day after anesthesia. There were 34 cases (85%) of mild nausea and vomiting within 24 hours after the operation in the hydromorphone group. In the morphine group, there were 16 cases (40%) of mild nausea and vomiting within 24 hours after the operation, 10 cases (25%) of severe nausea and vomiting., Conclusions: The occurrence of severe malignant vomiting after the use of morphine was more than that after the use of hydromorphone. Normal level and function of motilin is the basis of avoiding nausea and vomiting. Too fast or too slow gastrointestinal motility can induce postoperative nausea and vomiting.

Objective: To compare the efficacy and quality of analgesia provided by constant rate infusions (CRIs) of hydromorphone and fentanyl in dogs in the intensive care unit (ICU)., Study Design: Prospective, randomized, blinded, clinical trial., Animals: A total of 29 client-owned dogs., Methods: Dogs prescribed a μ-opioid agonist infusion for postsurgical or medical pain were randomized to be administered either hydromorphone (0.025 or 0.05 mg kg -1 bolus, followed by a 0.03 mg kg -1  hour -1 infusion) or fentanyl (2.5 or 5 μg kg -1 bolus, followed by a 3 μg kg -1  hour -1 infusion). The technical staff and clinicians were blinded as to which drug was administered. Pain scores, using the Colorado State University Canine Acute Pain Scale, sedation scores and nausea scores were assigned at regular intervals and compared between groups. Dose escalation and de-escalation of the study drug were performed according to set protocols. Adverse clinical signs and all other medications administered were recorded and compared between groups. The study drug was discontinued if the animal remained painful despite dose escalations, or if adverse effects were noted., Results: The pain scores were of low magnitude and were not significantly different between groups. The use of concurrent analgesia, sedation/anxiolytic medications and antacid/antiemetic medications was not different between groups. Sedation and nausea scores were not statistically different between groups., Conclusions and Clinical Relevance: Hydromorphone and fentanyl CRIs appear to be equally effective for adequate pain relief in dogs, with no significant differences in adverse effects. Therefore, either drug may be chosen for control of postsurgical or medical pain in an ICU setting., (Copyright © 2018 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Objective: To evaluate the safety and efficiency of patient-controlled intravenous analgesia (PCIA) using hydromorphone supplement with dexmedetomidine on patients undergoing transcatheter arterial chemoembolization. Methods: One hundred and eighty patients, age ranged from 40 to 65 years, body mass index from 18 to 25 kg/m(2,) ASA physical status Ⅱ-Ⅲ, who were scheduled for transcatheter arterial chemoembolization (TACE) under monitor anesthesia care (MAC) were randomly divided into 3 groups: hydromorphone group (H group), hydromorphone supplement with dexmedetomidine 1 μg/kg group (D1 group), hydromorphone supplement with dexmedetomidine 2 μg/kg group (D2 group), 60 patients in every group. All the groups of patients received PCIA pump, in the H group, the PCIA reagent was composed of 120 μg/kg hydromorphone and 5 mg tropisetron in 100 ml of normal saline. In comparison, PCIA regiment was composed of 120 μg/kg hydromorphone, 1 μg/kg dexmedetomidine and 5 mg tropisetron in 100 ml of normal saline in the D1 group, while 120 μg/kg hydromorphone, 2 μg/kg dexmedetomidine and 5 mg tropisetron in 100 ml of normal saline in the D2 group. The visual analogue scale (VAS) score, the observer's assessment of alertness/sedation scale (OAA/S) score, patients' satisfaction index, consumption of hydromorphone, the additional dose of morphine, the effective pressing times of PCIA and adverse reactions were recorded in detail at 0, 0.5, 1, 4, 12 and 24 hours after the patients underwent TACE. Results: The total consumptions of hydromorphone were (4.3±0.1), (4.1±0.1), and (3.8±0.1) mg in group H, D1, and D2, respectively, and the effective pressing times were 13±3, 6±2 and 2±1, the additional doses of morphine were (30±5), (15±3), and (3±1) mg, and adverse reaction rates were 45.0%, 28.3%, and 10.0%, respectively. The manifestations mentioned above in D2 group were significantly lower than those in group H and group D1 ( P <0.05). Immediately and 5 min after embolization, at the end of surgery and 0.5, 1, 4, 12 and 24 h after surgery, the VAS scores in the D2 group were 1.9±0.2, 2.1±0.3, 1.8±0.4, 1.8±0.3, 1.7±0.3, 1.6±0.3, 1.3±0.2, 1.3±0.3, respectively, lower than those in group H and group D1 ( P <0.05); The satisfaction index in D2 group at these times were 8.7±1.1, 8.9±0.8, 9.2±0.9, 9.0±0.7, 9.1±0.8, 9.0±0.6, 9.1±0.7, 9.2±0.9, respectively, higher than those in group H and group D1 ( P <0.05). No breath depression happened in these three groups. Conclusion: The formula of hydromorphone combined with dexmedetomidine to patients undergoing TACE is greatly safe and efficient, with advantages in alleviating pain, reducing hydromorphone consumption and the incidence of adverse reaction of hydromorphone, and without breath depression.