Summary Spinal anaesthesia is the preferred anaesthetic technique for elective Caesarean deliveries. Hypotension is the most common side-effect and has both maternal and neonatal consequences. Different strategies have been attempted to prevent spinal-induced hypotension, including the use of low-dose bupivacaine. We conducted a systematic search for randomized controlled trials comparing the efficacy of spinal bupivacaine in low dose (LD ≤8 mg) with conventional dose (CD >8 mg) for elective Caesarean delivery. Thirty-five trials were identified for eligibility assessment, 15 were selected for data extraction, and 12 were finally included in the meta-analysis. We investigated sources of heterogeneity, subgroup analysis, and meta-regression for confounding variables (baricity, intrathecal opioids, lateral vs sitting position, uterine exteriorization, and study population). Sensitivity analysis was performed to test the robustness of the results. In the LD group, the need for analgesic supplementation during surgery was significantly higher [risk ratio (RR)=3.76, 95% confidence interval (95% CI)=2.38–5.92] and the number needed to treat for an additional harmful outcome (NNTH) was 4 (95% CI=2–7). Furthermore, the LD group exhibited a lower risk of hypotension (RR=0.78, 95% CI=0.65–0.93) and nausea/vomiting (RR=0.71, 95% CI=0.55–0.93). Conversion to general anaesthesia occurred only in the LD group (two events). Neonatal outcomes (Apgar score, acid–base status) and clinical quality variables (patient satisfaction, surgical conditions) showed non-significant differences between LD and CD. This meta-analysis demonstrates that low-dose bupivacaine in spinal anaesthesia compromises anaesthetic efficacy (risk of analgesic supplementation: high grade of evidence), despite the benefit of lower maternal side-effects (hypotension, nausea/vomiting: moderate grade of evidence).

Efficacy of low-dose bupivacaine in spinal anaesthesia for Caesarean delivery: systematic review and meta-analysis

Objectives To compare the maximum change in numeric rating scale (NRS) pain scores, in patients receiving low-dose ketamine (LDK) or morphine (MOR) for acute pain in the emergency department. Methods We performed an institutional review board–approved, randomized, prospective, double-blinded trial at a tertiary, level 1 trauma center. A convenience sample of patients aged 18 to 59 years with acute abdominal, flank, low back, or extremity pain were enrolled. Subjects were consented and randomized to intravenous LDK (0.3mg/kg) or intravenous MOR (0.1mg/kg). Our primary outcome was the maximum change in NRS scores. A sample size of 20 subjects per group was calculated based on an 80% power to detect a 2-point change in NRS scores between treatment groups with estimated SDs of 2 and an α of .05, using a repeated-measures linear model. Results Forty-five subjects were enrolled (MOR 21, LDK 24). Demographic variables and baseline NRS scores (7.1 vs 7.1) were similar. Ketamine was not superior to MOR in the maximum change of NRS pain scores, MOR=5 (confidence interval, 6.6-3.5) and LDK=4.9 (confidence interval, 5.8-4). The time to achieve maximum reduction in NRS pain scores was at 5minutes for LDK and 100minutes for MOR. Vital signs, adverse events, provider, and nurse satisfaction scores were similar between groups. Conclusion Low-dose ketamine did not produce a greater reduction in NRS pain scores compared with MOR for acute pain in the emergency department. However, LDK induced a significant analgesic effect within 5 minutes and provided a moderate reduction in pain for 2 hours.

Low-dose ketamine vs morphine for acute pain in the ED: a randomized controlled trial☆ , ☆☆

We have conducted a meta-analysis of the clinical effects of morphine and hydromorphone to compare their benefit in analgesia. Embase and Medline were searched with an end-date of June 2009 for randomized, controlled trials or observational studies that addressed comparative analgesic and side-effects or particular side-effects. Two researchers independently identified included studies and extracted the data. Estimates of opioid effects were combined by using a random-effects model. Meta-analysis of eight studies suggested that hydromorphone (494 patients) provides slightly better (P=0.012) clinical analgesia than morphine (510 patients). The effect-size was small (Cohen's d=0.266) and disappeared when one study was removed, although the advantage of hydromorphone was more evident in studies of better quality (Jadad's rating). Side-effects were similar, for example, nausea (P=0.383, nine studies, 456 patients receiving hydromorphone and 460 morphine); vomiting (P=0.306, six studies, 246 patients receiving hydromorphone and 239 morphine); or itching (P=0.249, eight studies, 405 patients receiving hydromorphone, 410 morphine). This suggests some advantage of hydromorphone over morphine for analgesia. Additional potential clinical pharmacological advantages with regard to side-effects, such as safety in renal failure or during acute analgesia titration, are based on limited evidence and require substantiation by further studies.

Comparative clinical effects of hydromorphone and morphine: a meta-analysis

Background The metabolism of opioids is critical to consider for multiple reasons. The most commonly prescribed opioid agents often have metabolites that are active and are the source of both analgesic activity and an increased incidence of adverse events. Many opioids are metabolized by cytochrome P450 enzymes. Polymorphisms in cytochrome P450 genes and inhibition or induction of cytochrome P450 enzymes by coadministered drugs may significantly impact the systemic concentration of opioids and their metabolites and the associated efficacy or adverse events. Methods This is a narrative review of the metabolism of various opioids that will highlight the impact of their active metabolites, and the potential impact of cytochrome P450 activity on analgesic activity. Results An understanding of "opioid metabolic machinery," cytochrome P450 activity, and drug-drug interactions in the context of opioid selection may benefit clinicians and patients alike. Conclusions A greater appreciation of the metabolism of commonly prescribed opioid analgesics and the impact of their active metabolites on efficacy and safety may aid prescribers in tailoring care for optimal outcomes.

The metabolism of opioid agents and the clinical impact of their active metabolites.

Objective:To review clinical trials of intravenous opioids for severe acute pain in the emergency department (ED) and to provide an approach for optimization of therapy.Data Sources:Articles were identified through a search of Ovid/MEDLINE (1948-August 2010), PubMed (1950-August 2010), Cochrane Central Register of Controlled Trials (1991-August 2010), and Google Scholar (1900-August 2010). The search terms used were pain, opioid, and emergency department.Study Selection and Data Extraction:The search was limited by age group to adults and by publication type to comparative studies. Studies comparing routes of administration other than intravenous or using non-opioid comparators were not included. Bibliographies of all retrieved articles were reviewed to obtain additional articles. The focus of the search was to identify original research that compared intravenous opioids used for treatment of severe acute pain for adults in the ED.Data Synthesis:At equipotent doses, randomized controlled trials have not s...

https://www.mascc.org/assets/documents/pain_intravenousOpioidsIn_ER.pdf

Intravenous Opioids for Severe Acute Pain in the Emergency Department

Background: Older adults (ie, those aged ≥65 years) are the fastest growing segment of the US population, with an estimated ~71 million expected by 2030. Over the past 10 years, there has been an 11% increase in the number of emergency department (ED) visits by older adults, and pain is their most common chief complaint. Objective: The goal of this study was to compare weight-based IV hydromorphone and IV morphine in adults aged ≥65 years presenting to the ED with acute, severe pain. Methods: This was a prospective, randomized, double-blind clinical trial of older adults with acute, severe pain at an adult, urban academic ED. Patients were randomly allocated to receive a single dose of 0.0075-mg/kg IV hydromorphone or 0.05-mg/kg IV morphine. The primary outcome was the between-group difference in decrease in pain from baseline to 30 minutes after the medications were infused. Patients' degree of pain was measured on a numerical rating scale (NRS) where “0” was defined as “no pain” and “10” was defined as “the worst pain possible.” Adverse effects, pain reduction at 10 minutes and 2 hours postbaseline, patient evaluations of satisfaction and pain relief at 30 minutes postbaseline, and use of additional analgesics and antiemetics were tracked as secondary outcomes. Results: A total of 194 patients were randomized to treatment; 183 patients (hydromorphone group, n = 93; morphine group, n = 90 [overall mean (SD) age, 75 (8) years]) had sufficient data for analysis at the primary end point of 30 minutes postbaseline. The mean decrease in pain from baseline to 30 minutes in patients allocated to IV hydromorphone was 3.8 versus 3.3 NRS units in patients allocated to IV morphine. This difference of 0.5 NRS unit (95% CI, −0.2 to 1.3) was neither clinically nor statistically significant. A majority of patients in both groups (57.0% randomized to hydromorphone and 58.9% randomized to morphine) failed to achieve a ≥50% reduction in pain within 30 minutes of treatment. The incidence of adverse effects from baseline to 30 minutes was not statistically different in the 2 groups. Conclusions: A single dose of IV hydromorphone at 0.0075 mg/kg was neither clinically nor statistically different from IV morphine at 0.05 mg/kg for the treatment of acute, severe pain at 30 minutes postbaseline in these older adults in the ED. The incidence of adverse effects was not statistically different. Our data suggest that hydromorphone and morphine in the doses given had similar efficacy and safety profiles in these older adults. Neither regimen provided ≥50% pain relief for the majority of patients. Future investigations of acute pain management in older adults should examine the efficacy and safety of higher initial (loading) doses of opioids titrated at frequent intervals until adequate analgesia is achieved.

Efficacy and safety profile of a single dose of hydromorphone compared with morphine in older adults with acute, severe pain: a prospective, randomized, double-blind clinical trial.

Angelo Baccelieri

Papers

Efficacy and safety profile of a single dose of hydromorphone compared with morphine in older adults with acute, severe pain: a prospective, randomized, double-blind clinical trial.