Dosing Opioids for Optimal Acute Pain Management

Introduction

Opioids are accepted as a cornerstone of acute pain management in the emergency department (ED). ED physicians are armed with a variety of opioid analgesics, including meperidine, morphine, hydromorphone, fentanyl, and methadone; each has different routes of administration, including intravenous (IV), intramuscular, oral, transdermal, subcutaneous, and transmucosal. The absence of an analgesic ceiling for pure opioid agonists allows for dosages to be titrated upward until satisfactory pain relief is achieved or adverse effects become intolerable.^[1] However, the optimum dose of IV opioid analgesics remains very controversial among practicing ED physicians. Recent data show large variations in initial dosing of morphine, hydromorphone, fentanyl, and meperidine.

Morphine

Emergency medicine textbooks commonly recommend that the initial analgesic dose of IV morphine should be 0.1 mg/kg.^[2,3] Intravenous morphine is typically started at 0.1 mg/kg, with subsequent doses of 0.05 mg/kg given every 5 minutes until pain is relieved.^[4]

In an attempt to quantify the analgesic effect of a single 0.1-mg/kg dose of IV morphine, Bijur and colleagues^[5] showed that 67% of patients who received this dose reported less than 50% reduction in pain 30 minutes after administration. Thus, the standard 0.1-mg/kg dose of IV morphine is not adequate to control severe pain in most patients. In another study, 47% of patients presenting to the ED with painful conditions and who required IV opioids did not achieve 50% or greater reduction in pain 1 hour after administration of 0.1 mg/kg of morphine.^[6]

In a study by Bailey and colleagues^[7] that evaluated the efficacy of IV morphine in children with right lower quadrant pain, the initial dose of 0.1 mg/kg with a maximum dose of 5 mg was no more effective than placebo in diminishing children's pain 30 minutes after administration. Birnbaum and associates^[6] conducted a double-blind, placebo-controlled trial comparing the pain relief and safety of morphine 0.1 mg/kg with morphine 0.15 mg/kg in adult ED patients with acute pain. The primary outcome measure was the difference in numeric pain rating scale from baseline to 60 minutes. The results showed no significant difference between the 2 groups in the reduction in pain intensity after 30 minutes, and a marginal difference after 60 minutes in the group randomly assigned to receive the 0.15-mg/kg dose. Pain relief scores and adverse events were similar in the 2 groups, leading to the conclusion that morphine administration in a dose of 0.15 mg/kg does not demonstrate clinically significant superiority in pain relief over a dose of 0.1 mg/kg. However, the 0.15-mg/kg dose of morphine was administered in divided doses for reasons of patient safety, leaving open the possibility of a superior effect of a single 0.15-mg/kg loading dose of morphine compared with the conventional dose of 0.1 mg/kg.

In a search for the optimum dose of IV morphine, Lvovschi and colleagues^[8] evaluated the effect of IV morphine titration in treating severe pain in the ED. The study authors implemented a protocol with an initial dose of 2 mg (body weight < 60 kg) or 3 mg (body weight > 60 kg) with subsequent administration of 3 mg of morphine every 5 minutes until desirable or adverse effects occurred. The results showed pain relief in 99% of patients with a mean dose of morphine of 10.4 ± 6.2 mg; that is, 0.15 ± 0.09 mg/kg given in 3 boluses.

Key points about morphine.

The optimum single dose of morphine is yet to be determined.
A standard single dose of morphine of 0.1 mg/kg is inadequate to control acute pain in the ED.
Incremental titration of morphine with an initial loading dose of 0.1 mg/kg and subsequent dosages of 0.025 to 0.05 mg/kg every 5 minutes appears to be an acceptable alternative.
A higher initial (loading) dose of morphine at 0.15-0.2 mg/kg given either in a single dose over a few minutes or in divided doses may have potential for adequate pain relief but warrants further research.

Hydromorphone

Hydromorphone is an attractive choice in acute pain management in the ED because a fear still exists among ED physicians about administering weight-based doses of morphine, which can amount to 8-10 mg for the initial bolus. Burton and colleagues^[4] recommend using weight-based doses of hydromorphone at 0.015 mg/kg every 5 minutes to achieve pain relief.

Jasani and colleagues^[9] conducted one of the first studies to evaluate the use of hydromorphone in the ED. In a prospective, double-blind, randomized clinical trial comparing IV hydromorphone with IV meperidine in patients with renal colic, these investigators demonstrated the superiority of 1 mg of hydromorphone for pain relief at 15, 30, 60, and 120 minutes, with fewer side effects, vs 50 mg of meperidine. One of the drawbacks of the study was the use of fixed doses of medications instead of a weight-based approach.

Chang and colleagues^[10] conducted a randomized double-blinded study comparing IV hydromorphone (0.015 mg/kg) with IV morphine (0.1 mg/kg) in adult patients presenting to the ED in acute pain. The results showed that hydromorphone at a dose of 0.015 mg/kg gave better pain relief at 30 minutes. These investigators concluded that despite the minimal clinical significance reached in the study, hydromorphone can be a feasible alternative to 0.1 mg/kg of morphine. However, because it has been proven that morphine at a dose of 0.1 mg/kg does not provide adequate pain relief, serious questions remain about the potential efficacy of hydromorphone (0.015 mg/kg) as a single loading dose in relief of acute pain.

Chang and colleagues^[11] also evaluated the efficacy and safety of pain control in 223 adult patients using a "1+1" titration method, in which 1 mg of IV hydromorphone was administered as a loading dose with an additional 1 mg 15 minutes later, if requested by the patient. The results showed that 1 mg of hydromorphone followed by another 1-mg dose provided adequate analgesia in 96% of patients within 1 hour of administration. A subsequent study demonstrated that this patient-driven hydromorphone protocol was as clinically effective and safe as a traditional physician-driven protocol in the treatment of acute pain.^[12]

In an attempt to find an optimum dose of hydromorphone, Chang and colleagues^[13] evaluated the safety and efficacy of a single IV dose of 2 mg of hydromorphone administered to ED patients who presented with acute severe pain. The results showed a drastic reduction in the median pain score, from 10 to 1 within 5 minutes of medication administration, and to 0 at 30 minutes. None of the 269 patients enrolled in the study required naloxone; however, in 32% of patients, oxygen saturation fell below 95%.

Some experts advocate that opioid dosing in elderly patients should follow the principle of "start low and go slow."^[14] Chang and associates conducted a prospective, randomized, double-blind clinical trial in elderly patients with severe pain. They compared pain relief at 30 minutes following a weight-based, single dose of 0.0075 mg/kg of hydromorphone with a single dose of 0.05 mg/kg of morphine. Their findings showed no difference in pain relief between the aforementioned single dosages of hydromorphone and morphine; however, neither medication regimen achieved pain relief of at least 50%.^[15] This study raises a question about the benefits of using weight-based dosing for morphine and hydromorphone regardless of the patient's age.

Key points about hydromorphone.

A single dose of IV hydromorphone (0.015 mg/kg) is suboptimal in treating acute pain in the ED.
Titration with an initial bolus of 0.015 mg/kg and follow-up doses of 0.0075-0.015 mg/kg every 5-15 minutes might be a reasonable alternative, regardless of patient age.
A loading dose of 0.03 mg/kg is promising, although it was associated with transient hypoxia in a single study.
Further studies with larger loading doses of hydromorphone are needed, bearing in mind the severity of adverse effects of this opioid analgesic.

Fentanyl

Much of the data supporting IV administration of fentanyl in the ED come from studies of prehospital pain management and procedural sedation of adult and pediatric populations.^[16,17,18] Proposed doses of fentanyl in these studies vary from 1 µg/kg to 3 µg/kg.^[19] Literature that advocates the use of parenteral fentanyl for acute painful conditions in the ED can be found, but there is no general consensus on the optimum dose.

In a study comparing a prehospital fentanyl administration with morphine (0.1 mg/kg), fentanyl in a dose of 1 µg/kg with additional doses of 30 µg every 5 minutes achieved similar reductions in pain scores as morphine at 30 minutes and provided excellent analgesia to 76% of the patients.^[20]

Curtis and colleagues^[21] demonstrated significant improvement in the onset of analgesia with a fentanyl-based protocol in trauma patients. The proposed dose of fentanyl was 25-50 µg (for weight > 40 kg) and 10-25 µg (for weight < 40 kg) IV every 5 minutes. Cumulative doses of up to 150 µg did not result in any significant adverse effects.

A study evaluating drug efficacy and complications in pediatric patients who received continuous fentanyl infusions for postoperative pain (1 µg/kg/hour for 50 hours) demonstrated adequate analgesia in over 90% of patients without a single incidence of desaturation or a decrease in respirations that required emergency airway management.^[22] In a comparison of IV fentanyl in a dose of 1.5 µg/kg with nebulized fentanyl for acute pain management in children, Miner and colleagues^[23] demonstrated significant reductions in pain on a visual analog scale (from 82 mm to 26 mm) and no adverse effects.

In a study comparing the efficacy of nebulized vs IV fentanyl for the relief of abdominal pain, investigators showed that IV fentanyl at a dose of 1.5 µg/kg was associated with significant improvement in pain scores at 15 minutes but resulted in a need for a rescue medication in 50% of patients.^[24]

Key points about fentanyl.

The typical loading dose of IV fentanyl ordered by emergency physicians varies; further studies are needed to determine the optimum dose.
A loading dose of 1-1.5 µg/kg, with subsequent doses of 0.25-0.5 µg/kg every 15 minutes might be a good first alternative to morphine in treating acute painful conditions.
Direct comparisons of IV loading doses of fentanyl and morphine in randomized controlled trials are lacking.

Meperidine

The role of meperidine for acute pain management in the ED has been a subject of controversy, resulting in a tendency of physicians to avoid its use. Clark and colleagues^[25] demonstrated that the analgesic effect of meperidine was not superior to alternative parenteral pain medications in controlled trials; therefore, meperidine should be considered a second-line agent in the treatment of pain when opioid analgesics are required.

In a meta-analysis evaluating the efficacy of meperidine for the treatment of acute migraine, investigators cautioned that clinicians should consider alternatives to meperidine when parenteral analgesics are indicated.^[26] In a recent review of the role of meperidine in treating acute painful sickle cell crisis, Bradshaw and colleagues^[27] recommended limiting the use of this drug to 48 hours and using less than 600 mg in 24 hours. Despite the available data, no optimum dose of intravenous meperidine has been established for the treatment of acute painful conditions in the ED.

Henderson and colleagues^[28] compared IV ketorolac with meperidine for treatment of biliary colic. A dose of 50 mg of meperidine provided similar pain relief as ketorolac but caused more nausea and dizziness. A similar dose of meperidine was used in a study by Cordell and colleagues^[29] to compare IV ketorolac with meperidine for the treatment of acute renal colic.

Eray and colleagues^[30] compared a single dose of IV tramadol (50 mg) with a single dose of meperidine (50 mg) in patients with renal colic and found that 48% of meperidine patients required an additional rescue dose of 50 mg, compared with 67% of tramadol patients. Meperidine was judged superior to tramadol for the relief of acute pain associated with renal colic. In this study, the empiric loading dose of meperidine (50 mg) is not supported by the drug's pharmacokinetics or by an equianalgesic dosage conversion. Meperidine produces pain relief for a maximum of 3 hours, so in order to provide pain relief equivalent to 10 mg of morphine given every 4 hours, meperidine should be given in a dose of 100-150 mg every 3 hours.^[31] However, the current trend towards avoiding meperidine would discourage most ED physicians from administering meperidine at these doses.

Key points about meperidine.

Current literature does not support the use of IV meperidine as a first-line opioid analgesic, mostly as a result of severe neurotoxic effects.
Loading doses of 1-1.5 mg/kg, with additional titration, are supported by the pharmacologic properties of meperidine but might need to be reduced in elderly patients because of the drug's renal and neurotoxic effects.

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