Randomized Double-Blind Placebo-Controlled Trial of Two Intravenous Morphine Dosages (0.10 mg/kg and 0.15 mg/kg) in Emergency Department Patients With Moderate to Severe Acute Pain

doi:10.1016/j.annemergmed.2006.06.030

Annals of Emergency Medicine

Volume 49, Issue 4, April 2007, Pages 445-453.e2

https://doi.org/10.1016/j.annemergmed.2006.06.030 Get rights and content

Study objective

We compare pain relief and safety of morphine 0.10 mg/kg with 0.15 mg/kg in adult emergency department (ED) patients with acute pain.

Methods

This was a randomized double-blind placebo-controlled trial of intravenous morphine 0.10 mg/kg versus 0.15 mg/kg, (delivered in 2 divided doses) in adult ED patients with acute pain requiring opioid analgesia. Assessment was made at baseline, 30 minutes, and 60 minutes with a validated verbal numeric rating scale. Pain reduction and satisfaction scores were measured at 30 and 60 minutes. The primary outcome measure was the between-group difference in mean before-after change in numeric rating scale from baseline to 60 minutes.

Results

Two hundred eighty patients were enrolled. Between-group difference in numeric rating scale improvement from baseline to 60 minutes was 0.8 (95% confidence interval 0.1 to 1.5), favoring the 0.15 mg/kg group. Pain relief scores and adverse events were similar in the 2 groups.

Conclusion

Although 0.15 mg/kg of morphine is safe and provides statistically superior analgesia compared with a dose of morphine at 0.10 mg/kg, this difference in pain reduction did not reach the threshold of greater than 1.3 numeric rating scale units required to declare the higher dose of morphine clinically superior.

Introduction

Acute pain is a common emergency department (ED) problem.¹ Patients understandably expect a high degree of pain relief.2, 3 However, “oligoanalgesia” has been demonstrated repeatedly since Wilson and Pendleton⁴ coined the term in 1989 to describe the common practice of inadequate analgesia in the ED.

Morphine is the generally accepted standard for management of acute pain in the ED. However, recommended doses vary substantially, and there has been little systematic evaluation of dosing. Despite the common recommendation of 0.10 mg/kg starting dose of morphine, Bijur et al⁵ recently reported that 67% (95% confidence interval [CI] 58% to 76%) of ED patients receiving this dose for the treatment of acute pain reported a less than 50% decrease in pain 30 minutes after administration. These authors concluded that the standard 0.10 mg/kg dose of morphine may be too low to adequately control acute severe pain in the majority of patients.⁵ We were unable to identify published studies conducted in the ED systematically comparing different dosages of morphine for the treatment of acute pain. A postoperative morphine titration study found the mean morphine requirement for adequate analgesia to be 0.17 mg/kg, a dose substantially higher than that commonly administered in the ED.⁶ However, these findings observed in a postoperative setting may not be generalizable to pain in the ED.

If administration of higher dose morphine, ie, 0.15 mg/kg, is associated with greater pain relief than the lower but commonly recommended dose of 0.10 mg/kg, without more adverse effects or events, then this would provide support for administration of higher doses of morphine during the early phase of acute severe pain management.

The primary goal of this investigation was to compare pain relief and safety of 2 dosages of morphine sulfate (0.10 mg/kg and 0.15 mg/kg) in adult ED patients with acute pain. The primary outcome measure was the between-group difference in mean before-after change in numeric rating scale from baseline to 60 minutes. Secondary measures included pain reduction and satisfaction scores.

The a priori hypothesis was that administration of 0.15 mg/kg of morphine would be associated with clinically and statistically greater mean pain reduction than 0.10 mg/kg. According to extensive previous work, the minimum clinically significant difference in pain reduction has been determined to be 1.3 to 1.5 on the standard numeric rating scale (corresponding to 13 to 14 mm on the visual analog scale).7, 8, 9, 10

Section snippets

Study Design

A randomized double-blind placebo-controlled trial of intravenous morphine sulfate at 0.10 mg/kg versus 0.15 mg/kg was performed in adult ED patients with acute pain requiring opioid analgesia.

Setting

The study was conducted in the adult ED of Montefiore Medical Center, an urban academic center with approximately 80,000 adult visits per year, during March 25, 2005, to January 3, 2006. Data collection was performed by trained research associates available 24 hours per day, 7 days per week.

Selection of Participants

Patients 21 to

Results

Participant flow is summarized in the CONSORT diagram (Figure 1). Of 558 patients assessed for eligibility, 280 were enrolled in the study. Random allocation resulted in 138 patients assigned to the 0.10 mg/kg morphine group and 142 assigned to the 0.15 mg/kg group. All randomized patients received the initial morphine dose of 0.10 mg/kg, with the exception of 1 patient in the 0.15 mg/kg group who was noted to have a systolic blood pressure of 88 mm Hg after administration of 1.5 mg of the

Limitations

We chose a 0.10 mg/kg dose of morphine as a basis for comparison because of its common recommendation as an initial analgesic dose.14, 15, 16 A 50% increase in dose was chosen for comparison because of its postulated potential for superior effect without compromising safety. Our inability to demonstrate a clinically significant difference in analgesic effect for the 2 groups does not allow us to conclude whether the maximum effect of morphine was reached at 0.10 mg/kg for most patients or

Discussion

This study was designed to systematically evaluate the analgesic efficacy and safety of 2 dosages of morphine sulfate (0.10 mg/kg and 0.15 mg/kg) in adult ED patients with acute pain. We did not demonstrate clinically significant superiority in pain relief of 0.15 mg/kg morphine over the commonly recommended dose of 0.10 mg/kg, as measured by the difference between the 2 groups in mean pain reduction on the numeric rating scale from baseline to 60 minutes. Pain relief scores similarly were not

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Cited by (57)

Sex differences in the response to opioids for pain relief: A systematic review and meta-analysis
2019, Pharmacological Research
There are conflicting results about sex differences in the response to opioids for pain control and the role of potential influencing factors of these differences has not been investigated. We meta-analyzed differences and similarities between men and women in opioid response for pain control and investigated the potential influence of baseline pain intensity, age, body weight, and other factors in these findings.
PubMed, Scopus, and Cochrane CENTRAL were searched through January 15, 2019, for clinical studies in which opioids were administered for pain control. We included clinical studies in which (a) opioids were used to treat acute or chronic pain, (b) the response to opioids was broken down for men and women, and (c) the response to opioids was reported as (i) difference between baseline and final Visual Analog Scale of Pain Intensity (VASPI) score 30 min after opioid administration (Delta-VASPI at 30′), or daily dose of opioids (ii) self-administered by patients (patient-controlled analgesia PCA), or (iii) administered by physicians. Risk of bias was evaluated using ROBINS-I and the overall quality of evidence for primary outcomes was evaluated using the GRADE system.
Globally, we included 40 comparisons (6794 patients). Regarding acute pain, we found moderate quality of evidence that women and men do not differ in their response to opioids 30 min after their administration [Delta-VASPI at 30′: mean difference, MD = 0.42 (−0.07; 0.91)]. We also found moderate quality of evidence that women self-administer lower daily amounts of opioids [daily PCA: standardized mean difference, SMD = −0.30 (−0.41; −0.18)]. Regarding chronic pain, we found low quality of evidence that women receive lower daily doses for non-cancer pain [MD = −36.42 (−57.86; –14.99)]. By contrast, we found very low quality of evidence that women and men do not differ in the daily dose of opioids for cancer pain [MD = −16.09 (−40.13; 7.94)]. Age, comorbid mental disorders, type of administration, type of opioids, type of patients, and body weight significantly modified these results.
In conclusion, the results of the present meta-analysis suggest that men and women may differ in the response to opioids for pain relief, but these differences as well as similarities are significantly influenced by factors like age and comorbid mental disorders. However, the role of these factors is not usually evaluated in the prescription of opioids for pain control. There is an urgent need to conduct clinical trials on the use of opioid medications for pain, in which information about all possible influencing factors are provided and broken down for men and women.
Does co-treatment with ultra-low-dose naloxone and morphine provide better analgesia in renal colic patients?
2019, American Journal of Emergency Medicine
This study attempted to evaluate the efficacy of ultra-low-dose intravenous (IV) naloxone combined with IV morphine, as compared to IV morphine alone, in terms of reducing pain and morphine-induced side effects in patients with renal colic.
In this double-blind clinical trial, 150 patients aged 34 to 60 years old who presented to the emergency department (ED) with renal colic were randomly allocated to either an intervention group that received ultra-low-dose IV naloxone combined with IV morphine or to a control group that received morphine plus a placebo. The severity of pain, sedation, and nausea were assessed and recorded for all patients at entrance to the ED (T1), then at 20 (T2), 40 (T3), 60 (T4), 120 (T5), and 180 (T6) minutes after starting treatment. The Numeric Rating Scale (NRS) was used for the assessment of pain and nausea intensities, and the Ramsay Sedation Scale (RSS) was used to assess sedation.
A GEE model revealed that patients in the naloxone group had non-significantly reduced pain scores compared to those in the morphine group (coefficient = −0.68; 95% CI: −1.24 to −0.11, Wald X2 (1) = 5.41, p = 0.02). The sedation outcome demonstrated no statistically significant differences at T1 to T4 among patients with renal colic compared to the ones who only received morphine. At T5 and T6, 1.5% vs. 20% and 1.5% vs. 16.9% of subjects from the naloxone group versus the morphine group obtained RSS scores equal to 3, respectively (p = 0.001 and p = 0.004, respectively).
Compared to patients who only received IV morphine, co-treatment of ultra-low-dose naloxone with morphine could not provide better analgesia and sedation/agitation states in renal colic patients.
Essential pharmacologic options for acute pain management in the emergency setting
2019, Turkish Journal of Emergency Medicine
Citation Excerpt :
A ‘start low, go slow’ approach is often advised to prevent overdosing. However, substandard dosing may fail to achieve pain reduction as even standard dosing (0.1 mg/kg IV) has been demonstrated to leave up to two-thirds patients with insufficient pain reduction 30 min post-administration.105,106 A comparison of the standard-dose (0.10 mg/kg) versus higher-dose (0.15 mg/kg) IV morphine showed a statistically significant improvement in pain reduction with the higher dose, though the clinically significant minimum of 1.3 NRS unit difference between the two doses was not seen.8,106
Pain is the root cause for the overwhelming majority of emergency department (ED) visits worldwide. However, pain is often undertreated due to inappropriate analgesic dosing and ineffective utilization of available analgesics. It is essential for emergency providers to understand the analgesic armamentarium at their disposal and how it can be used safely and effectively to treat pain of every proportion within the emergency setting. A ‘balanced analgesia’ regimen may be used to treat pain while reducing the overall pharmacologic side effect profile of the combined analgesics. Channels-Enzymes-Receptors Targeted Analgesia (CERTA) is a multimodal analgesic strategy incorporating balanced analgesia by shifting from a system-based to a mechanistic-based approach to pain management that targets the physiologic pathways involved in pain signaling transmission. Targeting individual pain pathways allows for a variety of reduced-dose pharmacologic options – both opioid and non-opioid – to be used in a stepwise progression of analgesic strength as pain advances up the severity scale. By developing a familiarity with the various analgesic options at their disposal, emergency providers may formulate safe, effective, balanced analgesic combinations unique to each emergency pain presentation.
Use of Ultrasound-Guided Superficial Cervical Plexus Block for Pain Management in the Emergency Department
2018, Journal of Emergency Medicine
Although use of the superficial cervical plexus block (SCPB) by anesthesia for perioperative indications is well described, there is a paucity of research on use of SCPB in the emergency department (ED).
This prospective observational study aims to prospectively characterize the feasibility, potential for efficacy, and safety of ultrasound-guided SCPB in a convenience sample of ED patients presenting with painful conditions of the “cape” distribution of the neck and shoulder.
Data were gathered prospectively on a convenience sample of 27 patients presenting to a community ED with painful conditions involving the distribution of the SCPB: para-cervical muscle spasm/pain (n = 8), clavicle fractures (n = 7), acromioclavicular joint injuries (n = 3), radicular pain (n = 3), and rotator cuff disorders (n = 6). Pre- and post-block 11-point verbal numeric pain scores (VNPS) were recorded, as was the incidence of any immediate complications. A retrospective chart review looked for delayed complications in the 14-day post-block period.
The mean 11-point VNPS reduction was 5.4 points (62%). There were no early serious complications and one case each of self-limiting vocal hoarseness and asymptomatic hemi-diaphragmatic paresis. No delayed block-related complications were found.
While limited by the fact that this was a nonrandomized observational experience with no control group, our findings suggest that SCBP may be safe and have potential for efficacy, and warrants further evaluation in a randomized controlled trial.
Sufentanil sublingual tablet 30 mcg for moderate-to-severe acute pain in the ED
2018, American Journal of Emergency Medicine
Pharmacological properties of the sufentanil sublingual tablet 30 mcg (SST 30 mcg) could offer potential analgesic advantages in settings requiring noninvasive, acute pain management. The feasibility of using SST 30 mcg for moderate-to-severe pain management in the emergency department (ED) was evaluated.
This open-label, multicenter feasibility study included patients aged ≥ 18 years who presented to the ED with moderate-to-severe pain (≥ 4 on the numeric rating scale of pain intensity (NRS); opioid-tolerant patients were excluded. Patients received a single SST 30-mcg dose (single-dose cohort) or, upon request, ≤ 3 additional doses ≥ 60 min apart (multiple-dose cohort) and were evaluated over 1 or 2 h. Effectiveness was assessed by patient-reported pain scores (11-point NRS; 5-point pain relief scale). Safety and tolerability were also assessed.
Overall, 76 patients enrolled into the single-dose (n = 40) and multiple-dose (n = 36) cohorts. In the first hour (combined cohorts), mean pain intensity was significantly lower 15-min post-dosing (P < 0.001; clinically meaningful within 30-minutes post-dosing) and continued to decrease during the first hour (P < 0.001 for each 15-minute interval). Mean pain intensity (multiple-dose cohort) decreased from 7.6 at baseline to 4.5 at 1 h and to 4.6 at 2 h (P < 0.001 for both); mean pain relief increased from baseline to 1.9 at 1 h (P < 0.001) and to 2.0 at 2 h (P < 0.001). Most (79%) patients had no adverse events (AEs), and there were no severe AEs.
SST 30 mcg was feasible for managing moderate-to-severe acute pain in an ED setting.
The Treatment of Acute Pain in the Emergency Department: A White Paper Position Statement Prepared for the American Academy of Emergency Medicine
2018, Journal of Emergency Medicine
Pain is one of the most common reasons patients present to the emergency department (ED). Emergency physicians should be aware of the numerous opioid and nonopioid alternatives available for the treatment of pain.
To provide expert consensus guidelines for the safe and effective treatment of acute pain in the ED.
Multiple independent literature searches using PubMed were performed regarding treatment of acute pain. A multidisciplinary panel of experts in Pharmacology and Emergency Medicine reviewed and discussed the literature to develop consensus guidelines.
The guidelines provide resources for the safe use of opioids in the ED as well as pharmacological and nonpharmacological alternatives to opioid analgesia. Care should be tailored to the patient based on their specific acute painful condition and underlying risk factors and comorbidities.
Analgesia in the ED should be provided in the most safe and judicious manner, with the goals of relieving acute pain while decreasing the risk of complications and opioid dependence.

View all citing articles on Scopus

Supervising editor: Steven M. Green, MD

Author contributions: AB, DE, PEB, LH, and EJG conceived the study and designed the trial. DE supervised the conduct of the trial, the research associates, and data collection, including quality control. PB provided statistical advice on study design and analysis of the data. AB analyzed the data. PB conducted the interim analysis. AB drafted the article, and all authors contributed substantially to its revision. AB takes responsibility for the paper as a whole.

Funding and support: The authors report this study did not receive any outside funding or support.

Available online September 15, 2006.

Reprints not available from the authors.

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Pain management/original researchRandomized Double-Blind Placebo-Controlled Trial of Two Intravenous Morphine Dosages (0.10 mg/kg and 0.15 mg/kg) in Emergency Department Patients With Moderate to Severe Acute Pain

Study objective

Methods

Results

Conclusion

Introduction

Section snippets

Study Design

Setting

Selection of Participants

Results

Limitations

Discussion

Am J Emerg Med

Am J Emerg Med

Am J Emerg Med

Ann Emerg Med

Ann Emerg Med

Ann Emerg Med

Am J Emerg Med

Am J Emerg Med

Pain

J Pain

J Emerg Med

Ambulatory care visits to physician offices, hospital outpatient departments, and emergency departments: United States, 2001-02

Vital Health Stat

Relationships between measurement of pain using visual analog score and morphine requirements during postoperative intravenous morphine titration

Anesthesiology

Pain management/original research
Randomized Double-Blind Placebo-Controlled Trial of Two Intravenous Morphine Dosages (0.10 mg/kg and 0.15 mg/kg) in Emergency Department Patients With Moderate to Severe Acute Pain