Efficacy and safety of hydromorphone for cancer pain: a systematic review and meta-analysis.

BACKGROUND: Cancer pain significantly impacts individuals' quality of life, with opioids being employed as the primary means for pain relief. Nevertheless, concerns persist regarding the adverse reactions and effectiveness of opioids such as morphine. Hydromorphone, recognized as a potent opioid, is a viable alternative for managing cancer-related pain. The goal of this systematic review and meta-analysis was to determine the effectiveness and safety characteristics of hydromorphone in comparison to other opioids, as well as different methods of administering this medication within the scope of cancer pain treatment. METHODS: The PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases were searched on December 25th, 2023. Following the PRISMA guidelines, a systematic investigation of databases was carried out, and suitable studies were chosen according to predetermined criteria (PICO framework). The meta-analyses were performed using a random-effects model. RESULTS: This review included 18 RCTs with 2271 patients who compared hydromorphone with morphine, oxycodone, or fentanyl, as well as other types of hydromorphone. Hydromorphone demonstrated efficacy similar to that of morphine and oxycodone in reducing cancer pain intensity, decreasing additional analgesic consumption, and improving quality of life. However, morphine showed slight superiority over hydromorphone in reducing breakthrough pain. Adverse events were comparable between hydromorphone and morphine or oxycodone. Patient-controlled and clinician-controlled hydromorphone administration routes yielded similar outcomes. CONCLUSIONS: The outcomes of this study substantiate the efficacy of hydromorphone in the management of cancer-related pain, demonstrating similar levels of effectiveness and safety as morphine and oxycodone. These findings are consistent with prior comprehensive analyses, suggesting that hydromorphone is a feasible choice for alleviating cancer-associated pain. Additional investigations are warranted to determine its efficacy in distinct patient cohorts and for different modes of administration. TRIAL REGISTRATION: Prospero registration ID: CRD42024517513. Link: https://www.crd.york.ac.uk/PROSPERO/#recordDetails .

Effectiveness of Hydromorphone Hydrochloride Combined with Bupivacaine for Combined Spinal and Epidural Anaesthesia in Reducing Postpartum Urinary Retention: A Retrospective Study.

BACKGROUND: Postpartum urinary retention is a common complication following caesarean section, with significant implications for patient comfort and recovery. Combined spinal and epidural anaesthesia is frequently employed for caesarean section, but postpartum urinary retention remains a clinical concern despite its benefits. This study aimed to investigate the effectiveness of hydromorphone hydrochloride combined with bupivacaine for combined spinal and epidural anaesthesia in reducing postpartum urinary retention. METHODS: A retrospective analysis was conducted on patients who received combined spinal and epidural anaesthesia for caesarean section. The control group received bupivacaine, whereas the hydromorphone hydrochloride combined with bupivacaine spinal-epidural anaesthesia (HB) group received hydromorphone hydrochloride combined with bupivacaine. Data on demographics, anaesthesia, operative characteristics, postoperative urinary retention and adverse events were collected and analysed. RESULTS: The study enrolled 105 patients, with a control group (n = 51) receiving bupivacaine spinal-epidural anaesthesia and an observation group (n = 54) receiving hydromorphone hydrochloride combined with bupivacaine spinal-epidural anaesthesia. The incidence of postoperative urinary retention was significantly lower in the HB group than in the control group (3.70% vs. 17.65%, p = 0.044). Furthermore, the HB group exhibited a shorter time to first voiding after anaesthesia (5.72 ± 1.26 h vs. 6.28 ± 1.35 h, p = 0.029), lower peak postvoid residual volume (168.57 ± 25.09 mL vs. 180.43 ± 30.21 mL, p = 0.032), decreased need for postoperative catheterisation (5.56% vs. 21.57%, p = 0.034) and shorter duration of urinary catheterisation (10.92 ± 2.61 h vs. 12.04 ± 2.87 h, p = 0.039) than the control group. Correlation analysis supported a negative correlation between hydromorphone supplementation and parameters related to postoperative urinary retention. Multivariate regression analysis demonstrated a significant association between the duration of urinary catheterisation and the use of hydromorphone with the occurrence of postoperative urinary retention, providing further insights into the multifactorial nature of this postoperative complication. CONCLUSIONS: The addition of hydromorphone hydrochloride to bupivacaine for combined spinal and epidural anaesthesia was associated with a reduced incidence of postpartum urinary retention and improved postoperative voiding parameters, without significantly increasing the risk of adverse events.

Transient Acute Diplopia as a Rare Side Effect of Hydromorphone: A Case Report.

Diplopia, or double vision, has been listed as a rare adverse effect of intravenous hydromorphone, although there are no case studies or literature documenting this. We detail a case of acute transient diplopia correlated with the use of intraoperative hydromorphone and postoperative hydromorphone patient-controlled analgesia. Although the mechanism for this adverse effect is unknown, there may be risk factors that predispose patients to the potential toxic metabolic effects of hydromorphone. We share the first published case of diplopia as a clinically relevant adverse effect of hydromorphone and propose a potential reason behind this association.

Gastrointestinal adverse effects associated with the use of intravenous oliceridine compared with intravenous hydromorphone or fentanyl in acute pain management utilizing adjusted indirect treatment comparison methods.

Background: In the absence of head-to-head comparative data from randomized controlled trials, indirect treatment comparisons (ITCs) may be used to compare the relative effects of treatments versus a common comparator (either placebo or active treatment). For acute pain management, the effects of oliceridine have been compared in clinical trials to morphine but not to fentanyl or hydromorphone. Aim: To assess the comparative safety (specifically differences in the incidence of nausea, vomiting and opioid-induced respiratory depression [OIRD]) between oliceridine and relevant comparators (fentanyl and hydromorphone) through ITC analysis. Methods: A systematic literature review identified randomized clinical trials with oliceridine versus morphine and morphine versus fentanyl or hydromorphone. The ITC utilized the common active comparator, morphine, for the analysis. Results: A total of six randomized controlled trials (oliceridine - 2; hydromorphone - 3; fentanyl - 1) were identified for data to be used in the ITC analyses. The oliceridine data were reported in two studies (plastic surgery and orthopedic surgery) and were also reported in a pooled analysis. The ITC focused on nausea and vomiting due to limited data for OIRD. When oliceridine was compared with hydromorphone in the ITC analysis, oliceridine significantly reduced the incidence of nausea and/or vomiting requiring antiemetics compared with hydromorphone (both orthopedic surgery and pooled data), while results in plastic surgery were not statistically significant. When oliceridine was compared with hydromorphone utilizing data from Hong, the ITC only showed a trend toward reduced risk of nausea and vomiting with oliceridine that was not statistically significant across all three comparisons (orthopedic surgery, plastic surgery and combined). An ITC comparing oliceridine with a study of fentanyl utilizing the oliceridine orthopedic surgery data and combined orthopedic and plastic surgery data showed a trend toward reduced risk that was not statistically significant. Conclusion: In ITC analyses, oliceridine significantly reduced the incidence of nausea and/or vomiting or the need for antiemetics in orthopedic surgery compared with hydromorphone and a non-significant trend toward reduced risk versus fentanyl.

Subcutaneous hydromorphone hydrochloride provides antinociception with transient adverse effects in four-toed hedgehogs (Atelerix albiventris).

OBJECTIVE: To evaluate the efficacy and safety of hydromorphone administered SC in four-toed hedgehogs (Atelerix albiventris). ANIMALS: 12 healthy adult hedgehogs. METHODS: Hedgehogs underwent 2 randomized, blinded, placebo-controlled, complete crossover studies. Hind limb withdrawal latencies in response to an acute thermal noxious stimulus were measured to evaluate the antinociceptive efficacy of hydromorphone. Baseline latencies were obtained prior to injection and collected again at 0.5, 1, 2, 4, and 6 hours following injection. Based on pilot studies, single doses of SC hydromorphone at 0.15 and 0.3 mg/kg were evaluated for efficacy in crossover trials. Safety of single (0.15 and 0.3 mg/kg) and multiple doses of hydromorphone (0.3 mg/kg, SC, q 4 h, for 3 doses) was also assessed. In addition to monitoring behavior during latency measurements, animals were evaluated for overt sedation and daily changes in food intake, body weight, and running wheel activity for 6 days after injection to evaluate for adverse effects. RESULTS: Hydromorphone at 0.15 mg/kg provided antinociception lasting < 4 hours, and 0.3 mg/kg provided antinociception lasting < 6 hours. Hydromorphone produced transient abnormal behaviors at both doses, including vocalization, chewing motions of the jaw, and paw raising. There were no statistically significant differences in body weight or running wheel activity between treatments for single or multiple doses of hydromorphone. Three doses of 0.3 mg/kg hydromorphone (q 4 h) produced a statistically significant decrease (median, -9.7%; range, -64% to 10%) in 6-day total food intake. CLINICAL RELEVANCE: Subcutaneous hydromorphone (0.15 to 0.3 mg/kg) can be used for short-term antinociception with transient adverse effects in hedgehogs.

Different doses of nalmefene combined with hydromorphone hydrochloride for postoperative analgesia after colorectal surgery: a randomized controlled study.

BACKGROUND: Hydromorphone hydrochloride has a satisfactory postoperative analgesic effect for patients with colorectal cancer but is accompanied by a relatively high incidence of adverse events. Low-doses of naloxone combined with opioids for patient-controlled analgesia can reduce the incidence of drug-related adverse events. Nalmefene is a more selective opioid receptor antagonist than naloxone. The aim of this study was to determine the impact of low-doses of nalmefene on the analgesic effect and incidence of adverse events of patients with hydromorphone patient-controlled analgesia (PCA) undergoing colorectal radical surgery. METHODS: Ninety-nine patients undergoing elective laparoscopic or hand-assisted laparoscopic radical surgery under general anaesthesia were randomly divided into three groups. Group N1 received hydromorphone hydrochloride 0.15 mg/kg + nalmefene 2 µg/kg; Group N2 received hydromorphone hydrochloride 0.15 mg/kg + nalmefene 0.5 µg/kg; and the control group (Group C) received hydromorphone hydrochloride 0.15 mg/kg. All medications were diluted to 100 ml with normal saline. The primary outcome was pain intensity at 12 h after surgery; the secondary outcomes were the occurrence of nausea, vomiting and pruritus and the total analgesic consumption of the PCA pump at 1 h, 6 h, 12 h, 24 and 48 h after surgery. RESULTS: The NRS scores of Group N1 (2 µg/kg) were significantly lower than those of Group C (P = 0.025), and no difference was found between group N2 and group C (P > 0.05). Among the three groups, the NRS scores of Group N1 (2 µg/kg) were significantly lower than those of Group C at 12 h (P = 0.01) and 48 h (P = 0.01) postoperatively. Compared with 12 h postoperatively, the NRS scores were lower at 24 h postoperatively in Group N1 and Group C (P < 0.05) and significantly lower at 48 h postoperatively in all three groups (P < 0.001). There was a significant difference in the incidence of pruritus among the three groups (P = 0.036). CONCLUSIONS: Nalmefene at a dosage of 2 µg/kg enhances the postoperative analgesic effect of hydromorphone hydrochloride and reduces the occurrence of postoperative pruritus. TRIAL REGISTRATION: The trial was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR2000033520, date: 03/06/2020).

Opioid Switch Dosing in Chronic Cancer Pain: A Prospective Longitudinal Study.

Background: Opioid switching is common, however, conversion tables have limitations. Guidelines suggest postswitch dose reduction, yet, observations show opioid doses may increase postswitch. Objectives: To document the opioid conversion factor postswitch in cancer, and whether pain and adverse effect outcomes differ between switched opioid groups. Design/Setting: This multicenter prospective longitudinal study included people with advanced cancer in Australia. Clinical data (demographics, opioids) and validated instruments (pain, adverse effects) were collected twice, seven days apart. Results: Opioid switch resulted in dose increase (median oral morphine equivalent daily dose 90 mg [interquartile range {IQR} 45-184] to 150 mg [IQR 79-270]), reduced average pain (5.1 [standard deviation {SD} 1.7] to 3.8 [SD 1.6]), and reduced adverse effects. Hydromorphone dose increased 2.5 times (IQR 1.0-3.6) above the original conversion factor used. Conclusions: Opioid switching resulted in overall dose increase, particularly when switching to hydromorphone. Higher preswitch dosing may require higher dose conversion ratios. Dose reduction postswitch risks undertreatment and may not be always appropriate.

Effects of S-ketamine added to patient-controlled analgesia on early postoperative pain and recovery in patients undergoing thoracoscopic lung surgery: A randomized double-blinded controlled trial.

STUDY OBJECTIVE: To investigate whether the addition of S-ketamine to patient-controlled hydromorphone analgesia decreases postoperative moderate-to-severe pain and improves the quality of recovery (QoR) in patients undergoing thoracoscopic lung surgery. DESIGN: Single-center prospective randomized double-blinded controlled trial. SETTING: Tertiary university hospital. PATIENTS: 242 patients undergoing thoracoscopic lung surgery. INTERVENTIONS: Patients were randomized to receive intravenous patient-controlled analgesia (IV-PCA) with hydromorphone alone or hydromorphone combined with S-ketamine (0.5 mg/kg/48 h, 1 mg/kg/48 h, or 2 mg/kg/48 h). MEASUREMENTS: Primary outcome was proportion of patients with moderate-to-severe pain. (numerical rating scale [NRS] pain scores ≥4 when coughing) within 2 days after surgery. Postoperative QoR scores and other prespecified outcomes were also recorded. MAIN RESULTS: Of 242 enrolled patients, 220 were included in the final analysis. The results demonstrated that the incidence of postoperative moderate-to-severe pain was significantly different between the hydromorphone group and combined S-ketamine group (absolute difference, 27.9%; 95% confidence interval [CI], 11.7% to 42.1%; P < 0.001). Patients who received S-ketamine had lower NRS pain scores at rest and when coughing on postoperative day 1 (POD1; median difference 1 and 1, P < 0.001) and postoperative day 2 (POD2; median difference 1 and 1, P < 0.001). The QoR-15 scores were higher in the combined S-ketamine group on POD1 (mean difference 6, P < 0.001) and POD2 (mean difference 6, P < 0.001) than in the hydromorphone group. A higher dose of S-ketamine was associated with deeper sedation. No differences were detected in the other safety outcomes. CONCLUSIONS: Addition of S-ketamine to IV-PCA hydromorphone significantly reduced the incidence of postoperative moderate-to-severe pain and improved the QoR in patients undergoing thoracoscopic lung surgery. TRIAL REGISTRATION: Chinese Clinical Trail Register (identifier: ChiCTR2200058890).

Prevalence of opioid-induced adverse events across opioids commonly used for analgesic treatment in Japan: a multicenter prospective longitudinal study.

PURPOSE: Although opioids have been shown to be effective for cancer pain, opioid-induced adverse events (AEs) are common. To date, little is known about the differences in risks of AEs by opioid type. This study was performed to compare the prevalence of AEs across opioids commonly used for analgesic treatment in Japan. METHODS: This study was conducted as a preplanned secondary analysis of a multicenter prospective longitudinal study of inpatients with cancer pain who received specialized palliative care for cancer pain relief. We assessed daily AEs until termination of follow-up. We rated the severity of AEs based on the Common Terminology Criteria for Adverse Events version 5.0. We computed adjusted odds ratios for each AE (constipation, nausea and vomiting, delirium, and drowsiness) with the following variables: opioid, age, sex, renal dysfunction, and primary cancer site. RESULTS: In total, 465 patients were analyzed. Based on the descriptive analysis, the top four most commonly used opioids were included in the analysis: oxycodone, hydromorphone, fentanyl, and tramadol. With respect to the prevalence of AEs among all analyzed patients, delirium (n = 25, 6.3%) was the most frequent, followed by drowsiness (n = 21, 5.3%), nausea and vomiting (n = 19, 4.8%), and constipation (n = 28, 4.6%). The multivariate logistic analysis showed that no single opioid was identified as a statistically significant independent predictor of any AE. CONCLUSION: There was no significant difference in the prevalence of AEs among oxycodone, fentanyl, hydromorphone, and tramadol, which are commonly used for analgesic treatment in Japan.

Retrospective Review of Intrathecal Hydromorphone Dose Range and Complications.

BACKGROUND: Optimal intrathecal dosing regimens for hydromorphone are not well established for analgesia after abdominal surgery. OBJECTIVES: We reviewed intrathecal hydromorphone doses and complications because dosing variability has been observed among anesthesiologists. We hypothesized that increasing doses of intrathecal hydromorphone would be associated with improved postoperative analgesia, but with increased rates of opioid-related adverse events. STUDY DESIGN: Retrospective analysis. SETTING: A high-volume academic referral center in the United States. METHODS: A retrospective study was conducted of adults undergoing abdominal surgery under general anesthesia supplemented preoperatively with intrathecal hydromorphone for postoperative analgesia from May 5, 2018, through May 31, 2021. Patients were categorized into 3 hydromorphone dosing groups: low-dose (50-100 µg), middle-dose (101-199 µg), and high-dose (200-300 µg). Multivariable logistic regression models were used to assess rates of severe postoperative pain, severe opioid-related adverse events, oversedation, and pruritus in the postanesthesia care unit (PACU) and within 24 hours after PACU discharge. RESULTS: Of 1,846 patients identified, 1,235 (66.9%) were in the low-dose group; 321 (17.3%), middle-dose group; and 290 (15.7%), high-dose group. Patients receiving the 2 higher doses had more extensive procedures. An unadjusted analysis showed differing rates of severe pain in the PACU by group: 306 (24.8%) in the low-dose, 73 (22.7%) middle-dose, and 45 (15.5%) in the high-dose group (P = 0.003); these differences, however, were no longer significant after an adjusted analysis (P = 0.34). Ten severe opioid-related events occurred; all were recognized in the PACU. Five events each occurred in the low-dose and high-dose groups versus none in the middle-dose group (P = 0.02). No other differences were identified with adjusted analyses. LIMITATIONS: Limitations of our study include its retrospective design and its conduct at a single center, along with the apparent, but difficult to characterize, treatment biases in hydromorphone dosing. CONCLUSIONS: No dose response was observed between intrathecal hydromorphone dose and postoperative analgesia, a finding that may reflect treatment bias. Higher rates of severe opioid-related events were detected for patients receiving high-dose hydromorphone in the PACU, but all other safety outcomes were similar between dosing regimens. KEY WORDS: Drug-related side effects, opioid analgesics, outcome assessment, postoperative pain, spinal injections.

Postoperative Catatonia After Fentanyl, Hydromorphone, and Ketamine Administration in a Patient Taking Sertraline: A Case Report.

Opioid-induced catatonia is underrecognized and poorly understood in the literature. An 81-year-old woman with chronic kidney disease stage III taking sertraline underwent surgery with general anesthesia, receiving fentanyl, hydromorphone, and ketamine. Postoperatively, she was unresponsive, rigid, and cataleptic with pinpoint pupils. Symptoms resolved with a naloxone infusion suggesting opioid-induced catatonia as the leading diagnosis. Differential diagnoses and etiologies discussed reveal a possible multifactorial catatonia mechanism involving opioids, ketamine, and serotonin. Anesthesiologists should consider these potential interactions when using opioids for management of vulnerable patients.

HYDROMORPHONE MITIGATES CARDIOPULMONARY BYPASS-INDUCED ACUTE LUNG INJURY BY REPRESSING PYROPTOSIS OF ALVEOLAR MACROPHAGES.

ABSTRACT: Introduction: Acute lung injury (ALI) is a devastating pulmonary illness with diffuse inflammatory responses. Hydromorphone (Hyd) is an opioid agonist used for relieving moderate-to-severe pain. The present work investigated the effect of Hyd on cardiopulmonary bypass (CPB)-induced ALI by regulating pyroptosis of alveolar macrophages (AMs). Methods: Rats were subjected to CPB, followed by Hyd treatment. The lung injury in rat lung tissues was appraised by the ratio of lung wet/dry weight (weight), histological staining, and the total protein concentrations in bronchoalveolar lavage fluid, and lung function was assessed by oxygenation index and respiratory index, and lung macrophage pyroptosis was observed by fluorescence staining. Alveolar macrophages were separated and pyroptosis was determined by western blot assay and enzyme-linked immunosorbent assay. The expression patterns of nuclear factor erythroid 2-related factor 2/heme oxygenase 1 (Nrf2/HO-1), nod-like receptor protein 3 (NLRP3), N-terminal gasdermin-D, and cleaved caspase-1 were examined by real-time quantitative polymerase chain reaction, western blot, and immunohistochemistry assays. The impact of NLRP3 or Nrf2 on pyroptosis of AMs and CPB-induced ALI was observed after treatment of nigericin (NLRP3 agonist) or ML385 (Nrf2 inhibitor). Results: Hyd attenuated CPB-induced lung injury as manifested by reductions in lung inflammation and edema, the scores of lung injury, the ratio of lung wet/dry weight, and the total protein concentrations in bronchoalveolar lavage fluid. Besides, Hyd repressed NLRP3 inflammasome-mediated pyroptosis of AMs after CPB treatment. Hyd upregulated Nrf2/HO-1 expression levels to repress NLRP3 inflammasome-mediated pyroptosis. Treatment of nigericin or ML385 counteracted the role of Hyd in ameliorating pyroptosis of AMs and CPB-induced ALI. Conclusions: Hyd alleviated NLRP3 inflammasome-mediated pyroptosis and CPB-induced ALI via upregulating the Nrf2/HO-1 pathway, which may be achieved by AMs.

Controlled-release hydromorphone and risk of infection in adults: a systematic review.

BACKGROUND: Preliminary evidence suggests that people who inject drugs (PWID) may be at an increased risk of developing infective endocarditis (IE), hepatitis C virus (HCV) infection, and/or human immunodeficiency virus (HIV) infection from hydromorphone controlled-release formulation. The hypothesized mechanism is related to insolubility of the drug, which promotes reuse, leading to contamination of injecting equipment. However, this relationship has not been confirmed. We aimed to conduct a systematic review including adult PWID exposed to controlled-release hydromorphone and the risk of acquiring IE, HCV, and HIV. METHODS: We searched MEDLINE, EMBASE, and Evidence Based Medicine reviews from inception until September 2021. Following pilot testing, two reviewers conducted all screening of citations and full-text articles, as well as abstracted data, and appraised risk of bias using the Newcastle-Ottawa scale and Effective Practice and Organization of Care tool. Equity issues were examined using the PROGRESS-PLUS framework. Discrepancies were resolved consistently by a third reviewer. Meta-analysis was not feasible due to heterogeneity across the studies. RESULTS: After screening 3,231 citations from electronic databases, 722 citations from unpublished sources/reference scanning, and 626 full-text articles, five studies were included. Five were cohort studies, and one was a case-control study. The risk of bias varied across the studies. Two studies reported on gender, as well as other PROGRESS-PLUS criteria (race, housing, and employment). Three studies focused specifically on the controlled-release formulation of hydromorphone, whereas two studies focused on all formulations of hydromorphone. One retrospective cohort study found an association between controlled-release hydromorphone and IE, whereas a case-control study found no evidence of an association. One retrospective cohort study found an association between the number of hydromorphone controlled-release prescriptions and prevalence of HCV. None of the studies specifically reported on associations with HIV. DISCUSSION: Very few studies have examined the risk of IE, HCV, and HIV infection after exposure to controlled-release hydromorphone. Very low-quality and scant evidence suggests uncertainty around the risks of blood-borne infections, such as HCV and IE to PWID using this medication.

Intravenous diclofenac and orphenadrine for the treatment of postoperative pain after remifentanil-based anesthesia : A double-blinded, randomized, placebo-controlled study.

BACKGROUND: Postoperative intravenous diclofenac reduces patient opioid demand and is commonly used in surgical units. Orphenadrine is mainly used in combination with diclofenac for musculoskeletal injuries and postoperative pain control. The objective of this study was to compare the analgesic efficacy of diclofenac-orphenadrine, diclofenac alone and saline. METHODS: We performed a double-blind, randomized, placebo-controlled, parallel-group, single-center clinical study investigating the opioid-sparing effect of a combination of diclofenac and orphenadrine versus diclofenac alone versus isotonic saline solution. Initially 72 patients were included and received total intravenous anesthesia during cruciate ligament surgery. All patients were postoperatively treated with a patient-controlled analgesia (PCA) device containing hydromorphone. Pharmacological safety was assessed by laboratory parameters, vital signs, and delirium detection scores. RESULTS: There was no significant difference between the groups in cumulative dose of PCA analgesics required after 24 h postsurgery, with 5.90 mg (SD ± 2.90 mg) in the placebo group, 5.73 mg (SD ± 4.75 mg) in the diclofenac group, and 4.13 mg (SD ± 2.57 mg) in the diclofenac-orphenadrine group. Furthermore, there was no significant difference between the groups in cumulative dose of PCA analgesics required 2 h postsurgery (n = 65). Mean dose of hydromorphone required after 2 h was 1.54 mg (SD ± 0.57 mg) in the placebo group, 1.56 mg (SD ± 1.19 mg) in the diclofenac-only group, and 1.37 mg (SD ± 0.78 mg) in the diclofenac-orphenadrine group. However, when comparing the diclofenac-orphenadrine group and the diclofenac group combined to placebo there was a significant reduction in PCA usage in the first 24 h postsurgery. In total, there were 25 adverse events reported, none of which were rated as severe. CONCLUSION: Orphenadrine-diclofenac failed to significantly reduce postoperative opioid requirements. However, in an exploratory post hoc analysis the diclofenac-orphenadrine and the diclofenac group combined versus placebo showed a tendency to reduce opioid demand in postoperative pain control. Further research is required to determine the value of orphenadrine as an adjuvant in a multimodal approach for postoperative pain management.

Recurrent Persistent Hiccups on Opioid Treatment: A Case Report and Literature Review.

Hiccups are a rare but potentially debilitating side effect of opioid treatment, with only a handful of reported cases in the medical literature. The pathophysiological mechanism linking opioids and hiccups is unknown, and a lack of evidence exists concerning the optimal management of the condition. We report on a 64-year-old man diagnosed with advanced renal cancer and painful osteolytic metastases, presenting persistent hiccups while on opioid treatment. Hiccups recurred after multiple challenges with codeine, morphine and hydromorphone on separate occasions. Hiccups ceased only after opioid discontinuation, although various pharmacological treatments were tried to shorten the duration of hiccups. Eventually, fentanyl was introduced and was well tolerated by the patient, without any recurrence of hiccups. The chronological correlation between opioid initiation and the onset of hiccups, as well as opioid discontinuation and the termination of hiccups leads to the conclusion that a causal role of codeine, morphine and hydromorphone in this occurrence is likely. Individual susceptibility probably plays a central role in the development of opioid-related hiccups. Opioid rotation is a promising strategy in the management of opioid-related hiccups, particularly when the mere discontinuation of the opioid is not a viable option, such as in the oncology and palliative care field.

Intramuscular alfaxalone with or without buprenorphine or hydromorphone provides sedation with minimal adverse effects in healthy rabbits (Oryctolagus cuniculus) in a randomized blinded controlled trial.

OBJECTIVE: To evaluate the effects of alfaxalone administered IM with or without buprenorphine or hydromorphone in healthy rabbits (Oryctolagus cuniculus). ANIMALS: 24 male rabbits undergoing elective orchiectomy between August 21, 2021, and November 6, 2021. PROCEDURES: In this controlled clinical trial, rabbits were randomly assigned to receive alfaxalone (4 mg/kg, IM) alone (group A; n = 8) or with buprenorphine (0.03 mg/kg, IM; group BA; 8) or hydromorphone (0.1 mg/kg, IM; group HA; 8). Vital signs and sedation scores were recorded immediately prior to (T0) and 10 minutes after (T1) treatment. Ease of IV catheter placement and pain scores were also evaluated. All rabbits received ketamine (2.5 mg/kg, IV), midazolam (0.13 mg/kg, IV), and meloxicam (0.5 mg/kg, SC) before orchiectomy but after IM treatments. Results were compared across groups with ANOVA or Fisher exact tests and across time with paired t tests. RESULTS: Sedation score, median time to recumbency, and ease of catheter placement did not differ among groups. Supraglottic airway device placement was possible for 1 rabbit in group A, 1 in group BA, and 2 in group HA. Mean respiratory rate at T1 versus T0 was significantly decreased for groups BA (63.8 vs 128.6 breaths/min) and HA (66.7 vs 123.2 breaths/min). Mean postoperative pain scores were significantly lower for rabbits in group HA (0.58), compared with those in groups A (2.25) and BA (2.06). CLINICAL RELEVANCE: All 3 treatments provided reliable sedation; however, alfaxalone (4 mg/kg, IM) combined with hydromorphone (0.1 mg/kg, IM) may be a better choice for painful procedures.

Effect of a Postoperative Multimodal Opioid-Sparing Protocol vs Standard Opioid Prescribing on Postoperative Opioid Consumption After Knee or Shoulder Arthroscopy: A Randomized Clinical Trial.

Importance: In arthroscopic knee and shoulder surgery, there is growing evidence that opioid-sparing protocols may reduce postoperative opioid consumption while adequately addressing patients' pain. However, there are a lack of prospective, comparative trials evaluating their effectiveness. Objective: To evaluate the effect of a multimodal, opioid-sparing approach to postoperative pain management compared with the current standard of care in patients undergoing arthroscopic shoulder or knee surgery. Design, Setting, and Participants: This randomized clinical trial was performed at 3 clinical sites in Ontario, Canada, and enrolled 200 patients from March 2021 to March 2022 with final follow-up completed in April 2022. Adult patients undergoing outpatient arthroscopic shoulder or knee surgery were followed up for 6 weeks postoperatively. Interventions: The opioid-sparing group (100 participants randomized) received a prescription of naproxen, acetaminophen (paracetamol), and pantoprazole; a limited rescue prescription of hydromorphone; and a patient educational infographic. The control group (100 participants randomized) received the current standard of care determined by the treating surgeon, which consisted of an opioid analgesic. Main Outcomes and Measures: The primary outcome was postoperative oral morphine equivalent (OME) consumption at 6 weeks after surgery. There were 5 secondary outcomes, including pain, patient satisfaction, opioid refills, quantity of OMEs prescribed at the time of hospital discharge, and adverse events at 6 weeks all reported at 6 weeks after surgery. Results: Among the 200 patients who were randomized (mean age, 43 years; 73 women [38%]), 193 patients (97%) completed the trial; 98 of whom were randomized to receive standard care and 95 the opioid-sparing protocol. Patients in the opioid-sparing protocol consumed significantly fewer opioids (median, 0 mg; IQR, 0-8.0 mg) than patients in the control group (median, 40.0 mg; IQR, 7.5-105.0; z = -6.55; P < .001). Of the 5 prespecified secondary end points, 4 showed no significant difference. The mean amount of OMEs prescribed was 341.2 mg (95% CI, 310.2-372.2) in the standard care group and 40.4 mg (95% CI, 39.6-41.2) in the opioid-sparing group (mean difference, 300.8 mg; 95% CI, 269.4-332.3; P < .001). There was no significant difference in adverse events at 6 weeks (2 events [2.1%] in the standard care group vs 3 events [3.2%] in the opioid-sparing group), but more patients reported medication-related adverse effects in the standard care group (32% vs 19%, P = .048). Conclusions and Relevance: Among patients who underwent arthroscopic knee or shoulder surgery, a multimodal opioid-sparing postoperative pain management protocol, compared with standard opioid prescribing, significantly reduced postoperative opioid consumption over 6 weeks. Trial Registration: ClinicalTrials.gov Identifier: NCT04566250.

Intravenous Patient-Controlled Analgesia Versus Oral Opioid to Maintain Analgesia for Severe Cancer Pain: A Randomized Phase II Trial.

BACKGROUND: Optimal analgesic maintenance for severe cancer pain is unknown. This study evaluated the efficacy and safety of intravenous patient-controlled analgesia (IPCA) with continuous infusion plus rescue dose or bolus-only dose versus conventional oral extended-release morphine as a background dose with normal-release morphine as a rescue dose to maintain analgesia in patients with severe cancer pain after successful opioid titration. METHODS: Patients with persistent severe cancer pain (≥7 at rest on the 11-point numeric rating scale [NRS]) were randomly assigned to 1 of 3 treatment arms: (A1) IPCA hydromorphone with bolus-only dose where dosage was 10% to 20% of the total equianalgesic over the previous 24 hours (TEOP24H) administered as needed, (A2) IPCA hydromorphone with continuous infusion where dose per hour was the TEOP24H divided by 24 and bolus dosage for breakthrough pain was 10% to 20% of the TEOP24H, and (B) oral extended-release morphine based on TEOP24H/2 × 75% (because of incomplete cross-tolerance) every 12 hours plus normal-release morphine based on TEOP24H × 10% to 20% for breakthrough pain. After randomization, patients underwent IPCA hydromorphone titration for 24 hours to achieve pain control before beginning their assigned treatment. The primary endpoint was NRS over days 1 to 3. RESULTS: A total of 95 patients from 9 oncology study sites underwent randomization: 30 into arm A1, 32 into arm A2, and 33 into arm B. Arm B produced a significantly higher NRS over days 1 to 3 compared with arm A1 or A2 (P<.001). Daily NRS from day 1 to day 6 and patient satisfaction scores on day 3 and day 6 were worse in arm B. Median equivalent-morphine consumption increase was significantly lower in A1 (P=.024) among the 3 arms. No severe adverse event occurred in any arm. CONCLUSIONS: Compared with oral morphine maintenance, IPCA hydromorphone for analgesia maintenance improves control of severe cancer pain after successful titration. Furthermore, IPCA hydromorphone without continuous infusion may consume less opioid.

Quantitative and rapid detection of morphine and hydromorphone at the point of care by an automated giant magnetoresistive nanosensor platform.

Opioids, such as morphine and hydromorphone, are common pain management drugs with a high risk for addiction and adverse effects when delivered in large doses or administered too frequently. Point-of-care (POC) tools provide a solution to combat these negative outcomes through active monitoring of opioid concentrations in clinical settings. We demonstrate that giant magnetoresistive (GMR) nanosensors offer a quantitative, sensitive, and rapid solution for low-cost, sample-to-answer opioid detection at the POC. We show the robust nature of GMR nanosensors by developing a competitive morphine assay and characterizing it in saliva, blood, and plasma. We then implemented the assay on a fully automated POC GMR platform and demonstrated its duality to detect either morphine or hydromorphone using only 180 µL of direct saliva without the need for pre-processing. In 35 min from sample addition to result, the automated platform was controlled via smartphone and had seamless transmission of results via Bluetooth. The fully automated POC assay had a limit of detection of 3.43 ng/mL for morphine and 3.49 ng/mL for hydromorphone. The low-cost, 80-plex GMR nanosensor array coupled with the automated POC platform enables future development of multiplexed drug screening tools that can be deployed in clinical settings using a wide variety of non-invasive matrices.