REBEL Cast Ep 43: Pain Control and Opioid Sparing Options in the ED

Background: In the United States we are not only seeing an opioid epidemic but also a shortage of IV opioid agents. For both reasons, it is important to find non-opioid options for common pain complaints seen in the ED.  Changing prescribing practices is difficult but an important step in minimizing opioid usage.  Current research suggests that even short term opioid use can cause a predisposition to subsequent opioid dependence. In the spirit of doing no harm, we as a healthcare community should look to find other less harmful ways to decrease pain and suffering.  In this episode, we will review four randomized clinical trials published in the past year on pain control to see if there is evidence to support other non-opioid options.

Episode 43 – Pain Control and Opioid Sparing Options in the ED

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Study #1: IN Ketamine vs IV Morphine for Renal Colic [1]

What They Did:

• Prospective randomized double-blind controlled trial in 40 patients with renal colic at 2 Iranian EDs
• Intranasal (IN) ketamine 1mg/kg + IV placebo vs Intravenous (IV) morphine 0.1mg/kg + IN placebo
• If no decreases in VAS after 30 minutes, IV fentanyl was used as rescue analgesia at a dose of 1 – 2ug/kg q5min and titrated to effect

Outcomes:

• Primary: Visual analogue scale (VAS) changes at 5, 15, and 30 min after drug injection
• Secondary: Adverse reactions and need for rescue analgesia

Inclusion:

• Age >15 years of age
• Presenting to the ED due to renal colic pain
• No need for surgical intervention for urolithiasis

Exclusion:

• Opioid addiction and prior use of analgesics (The period of time for prior use of analgesics was not specified)
• Pregnancy
• History of ketamine or morphine hypersensitivity
• Nasal occlusion
• SBP > 180 or < 90mmHg
• Respiratory distress
• Altered level of consciousness
• Unable to cooperate

Results:

• Mean VAS Baseline Score
  • Morphine Group: 7.40 +/- 1.18
  • Ketamine Group: 8.35 +/- 1.30
• Mean VAS at 5min
  • Morphine Group: 6.07 +/- 0.47
  • Ketamine Group: 6.87 +/- 0.47
• Mean VAS at 15min
  • Morphine Group: 5.24 +/- 0.49
  • Ketamine Group: 5.60 +/- 0.49
• Mean VAS at 30min
  • Morphine Group: 4.02 +/- 0.59
  • Ketamine Group: 4.17 +/- 0.59
• IV morphine 0.1mg/kg provided better analgesic effect in patients with renal colic at 5 minutes, but IN ketamine 1mg/kg provided equal analgesia at 15 and 30 minutes
• Adverse Reactions:
  • Morphine Group:
    • Hypotension: 40%
    • Emergency Phenomenon: 0%
  • Ketamine Group:
    • Hypotension: 0%
    • Emergence Phenomenon: 30%
  • Rescue Analgesia Required:
    • Morphine Group: 35%
    • Ketamine Group: 25%
    • Not Statistically Significant

Strengths:

• Prospective, randomized, double-blind and placebo-controlled study
• Block randomization with block sizes of 4
• Diagnosis of urolithiasis was made via pragmatic practices (i.e. Ultrasound evidence of renal stone and hematuria in urine, not CT scanning everyone)
• Treating emergency physician blinded to the study
• Used analysis of covariance in order to adjust for baseline differences in pain

Limitations:

• Small study
• Chief investigator and triage nurse were aware of the patients group assignment
• Sample size was too small to detect differences in adverse events
• Follow up was only 30 minutes and it is unclear if more rescue analgesia would be required after 2 – 4 hours when the medications begin to wear off.
• This study only evaluated renal colic and not other forms of acute pain
• Didn’t give standard treatment of nephrolithiasis (i.e. NSAIDs)

Discussion:

• Worthy of mention:
  • IN ketamine has 45% peak plasma level at <30min and a terminal half-life of around 2hrs
  • IV morphine has its analgesic effect in < 10 min with peak plasma level of 20 min and duration of action near 4hrs
  • 0.1mg/kg of IV morphine is the recommended starting dose, but should be understood that additional doses may be needed

Author Conclusion: “IN ketamine may be effective in decreasing pain in renal colic.”

Study Take Home Point: IN ketamine 1mg/kg provides effective analgesic effect in renal colic when compared to IV morphine 0.1 mg/kg, but there is a delay of approximately 10 minutes until comparable analgesic effect with IN ketamine

Study #2: Oral Opioid vs Oral Non-Opioid for Extremity Pain [2]

What They Did:

• Randomized controlled double-blind clinical trial conducted at 2 urban EDs in the US for acute extremity pain
• 411 patients with moderate to severe acute extremity pain
  • 400mg ibuprofen +1000mg acetaminophen
  • 5mg oxycodone + 325mg acetaminophen
  • 5mg hydrocodone + 300mg acetaminophen
  • 30mg codeine + 300mg acetaminophen

Outcomes:

• Primary: Between-group difference in decline in pain 2 hours after pain medication (Pain assessed by an 11-point numerical rating scale; 0 = No pain & 10 = Worst possible pain)
• Predefined minimum clinically important difference was 1.3 on the NR
• Secondary: Proportion of patients receiving rescue analgesics, and total amount of analgesics in morphine equivalent units

Inclusion:

• Adults ≥21 years – 64 years
• Presenting to the ED for acute extremity pain
• Required to have a clinical indication for radiological imaging (Based on judgment of the ED attending physician)

Exclusion:

• Past use of methadone
• Presence of a chronic condition requiring frequent pain management such as sickle cell disease
• Fibromyalgia
• Any neuropathy
• History of adverse reaction to any of the study medications
• Having taken opioids within the past 24 hours
• Having taken ibuprofen or acetaminophen within the past 8 hours
• Pregnancy
• Breastfeeding
• History of peptic ulcer disease
• Report of any prior use of recreational narcotics
• Medical condition that might affect metabolism of opioid analgesics, acetaminophen, or ibuprofen such as hepatitis, renal insufficiency, hypothyroidism, hyperthyroidism, Addison disease, or Cushing disease
• Presence of any medicine that might interact with 1 of the study medications (i.e. SSRIs or TCAs)

Results:

• Baseline mean NRS pain score = 8.7
• NRS Pain Score Decrease at 2 Hours:
  • Ibuprofen/Acetaminophen = 4.3 (95% CI 3.6 – 4.9)
  • Oxycodone/Acetaminophen = 4.4 (95% CI 3.7 – 5.0)
  • Hydrocodone/Acetaminophen = 3.5 (95% CI 2.9 – 4.2)
  • Codeine/Acetaminophen = 3.9 (95% CI 3.2 – 4.5)
  • No statistically or clinically significant between-group differences
• 73 patients (17.8%) received rescue analgesics within 2-hour period

Strengths:

• Study analgesics were taken under direct observation to confirm ingestion
• Research pharmacist performed stratified randomization in blocks of 8 using an online randomization generator
• Analgesics were masked by placing them into identical unmarked opaque capsules
• Nurses and Physicians were blinded to study medications
• All patients who were enrolled and met inclusion criteria were analyzed in the groups to which they were randomized

Limitations:

• Adverse events not assessed
• Follow up time limited to 2 hours, not allowing for the duration of analgesia to be assessed
• 18% of patients required rescue analgesia

Discussion:

• Interestingly in this study, the need for imaging was considered a proxy for more severe injury
• The doses of opioid used in the combination pills were low (i.e. 5mg) and may explain why there is no difference in analgesic effect when compared to non-opioid combination agents. It is important to note however that acetaminophen at 500mg and combination of opioid at 5mg may be a reasonable starting dose for opioid naïve patients
• The extremity injuries were generally minor (i.e. sprain, strain, contusion) with a smaller proportion of patients, approximately 20%, having a diagnosis of extremity fracture amongst the 4 groups.

Author Conclusion: “For patients presenting to the ED with acute extremity pain, there were no statistically significant or clinically important differences in pain reduction at 2 hours among single-dose treatment with ibuprofen and acetaminophen or with 3 different opioid and acetaminophen combination analgesics. Further research to assess adverse events and other dosing may be warranted.”

Study Take Home Point: It is fair to say that ibuprofen and acetaminophen non-opioid combination pills can reduce pain in mild to moderate extremity injuries, but unfortunately, in this methodologically well done study, an adequate optimal dose non-opioid combination pill was compared to a less than optimal inadequate dose opioid combination pill.

Study #3: IV Ketorolac vs IV Morphine vs IV Ketorolac + Morphine for Renal Colic [3]

What They Did:

• Single center, triple-blind, randomized clinical trial
• 300 patients with clinical diagnosis of acute renal colic and pain score greater than 4 on a 10cm visual analogue scale (VAS) score
• 0.1mg/kg morphine IV + 30mg ketorolac IV vs 0.1mg/kg morphine IV vs 30mg ketorolac IV
• Rescue analgesia (0.05mg/kg IV morphine) was administered for persistent pain (Pain score >4 on VAS) after 20 and 40 minutes of original intervention

Outcomes:

• Primary: Pain intensity measured on a 10-cm VAS before intervention and at 20 and 40 minutes after intervention
• Secondary: Amount of rescue analgesia, adverse effects

Inclusion:

• Adults 18 – 55 years of age
• Clinical diagnosis of acute renal colic
• Pain score of 5 or more measured by 10cm VAS

Exclusion:

• History of kidney or renal dysfunction
• Severe dehydration
• Pregnancy
• Breastfeeding
• Single kidney or kidney transplant
• History of peptic ulcers and gastrointestinal bleeding
• Receiving analgesics within 6 hours before presentation
• History of bleeding diathesis
• History of cardiovascular disease
• Use of angiotensin-converting enzyme inhibitor or angiotensin receptor blockers
• Anticoagulant medication or coagulation disorder
• History of drug dependence or current use of methadone or chronic consumption of tobacco and alcohol
• Peritonitis or presence of any peritoneal signs

Results:

• Pain Intensity Baseline: 8.36
• Pain Intensity After 40 Min
  • Morphine/Ketorolac: 3.01 +/- 0.98
  • Morphine Alone: 3.66 +/- 1.02
  • Ketorolac Alone: 3.68 +/- 0.88
• No statistical difference in adverse effects
• Rescue Analgesic at 40 Min:
  • Morphine/Ketorolac: 16%
  • Morphine Alone: 20%
  • Ketorolac Alone: 24%

Strengths:

• Computer based random digit generator used to randomize patients
• Drugs prepared in similar syringes which were opaque
• Treating physicians, nurses, and patients blinded to study groups
• No patients lost to follow up

Limitations:

• Single center study
• Only measured VAS scores
• Not powered to detect less than 5% differences
• Ketamine may lead to unblinding due to issues with ocular response
• Lots of exclusion criteria

Author Conclusion: “Balanced analgesia with morphine and ketorolac is more effective compared to morphine or ketorolac alone determine by lower pain scores after 40-min of injection and lower need for rescue analgesia.”

Study Take Home Point: Although the authors conclude that “balanced analgesia” with morphine and ketorolac is more effective than morphine or ketorolac alone, it is important to realize that the pain scores in all 3 groups was less than 4 and the need for rescue analgesia was only slightly more.  Therefore, a ketorolac first strategy may still appropriate, with the addition of an IV opioid only if pain is not adequately controlled.

Study #4: Regional Nerve Blocks for Hip Fractures [4]

What They Did:

• Multicenter, randomized controlled trial at 3 New York Hospitals
• 161 patients with hip fractures
• Ultrasound-guided, single injection, femoral nerve block administered by EM physicians followed by:
  • Placement of a continuous fascia iliaca block (FIB) by anesthesiologists within 24 hours or conventional analgesics (CA)
• Femoral Nerve Block: 20mL of 0.5% bupivacaine
• Continuous Fascia Iliaca Block: 15mL of 0.2% ropivacaine, followed by continuous infusion of 0.2% ropivacaine at 5mL/hr; Catheters removed after POD 3

Outcomes:

• Primary:
• Pain (0 – 10 scale) at 1 and 2 hours after ED admission, at rest, with transfers out of bed, and with walking on POD 3
• Distance walked on postoperative day (POD) 3
• Secondary:
• Opioid requirements
• Walking ability 6 weeks after discharge
• Opioid side effects (≥1 day of severe nausea, sedation, or mental cloudiness)

Inclusion:

• ≥60 years of age
• Radiographically confirmed hip fracture

Exclusion:

• Refused to participate
• Did not meet eligibility criteria

Results:

• Pain Score 2 Hours After ED Presentation
  • FIB: 3.5
  • CA: 5.3
• Pain Score at Rest on POD 3
  • FIB: 2.9
  • CA: 3.8
• Pain Score With Transfers on POD 3
  • FIB: 4.7
  • CA: 5.9
• Pain Score With Walking on POD 3
  • FIB: 4.1
  • CA: 4.8
• Distance Ambulated in 2 Minutes on POD 3
  • FIB: 170.6 ft
  • CA: 100.0 ft
• Walking and Stair Climbing Ability at 6 Weeks (Mean Functional Independence Measure Locomotion Score)
  • FIB: 10.3
  • CA: 9.1
• Opioid Side Effects:
  • FIB: 3% (Also 33 – 40% less parenteral morphine equivalents)
  • CA: 12.4%

Strengths:

• Multicenter randomized trial
• Patients randomized using a computer-generated, stratified, blocked randomization list
• Interviewers and trial investigators blinded to participant randomization status

Limitations:

• Patients only enrolled between the hours of 8am – 8pm Sunday – Friday
• No sham nerve blocks given in this study as it was considered unethical, potentially resulting in a placebo effect
• 10% of cFIB catheters were either discontinued or became dislodged
• 29% of the participants could not be contacted at 6 weeks
• Many hospitals won’t have device for continuous infusion available

Author Conclusion: “Femoral nerve blocks performed by emergency physicians followed by continuous fascia iliaca blocks placed by anesthesiologists are feasible and result in superior outcomes.”

Study Take Home Point: In patients 60 years of age or older, presenting to the ED with hip fractures, femoral nerve blocks followed by continuous fascia iliaca blocks result in better pain control, improved mobility, improved functional status at 6 weeks and significantly less opioid side effects when compared to IV opioid analgesia.

Clinical Bottom Lines:

• IN ketamine 1mg/kg provides effective analgesia in renal colic
• Ibuprofen 400mg combined with acetaminophen 1000mg can reduce pain in mild to moderate extremity injuries
• In renal colic, a ketorolac 15mg IV first strategy is still appropriate, with the addition of an IV opioid only if pain is not adequately controlled
• In patients 60 years of age or older, presenting to the ED with hip fractures, femoral nerve blocks with 20mL of 0.5% bupivacaine not only improves pain, but also increase mobility and functional outcomes with significantly less medication side effects when compared to IV opioid agents

References:

1. Farnia MR et al. Comparison of Intranasal Ketamine Versus IV Morphine in Reducing Pain in Patients with Renal Colic. Am J Emerg Med 2017. PMID: 27931762
2. Chang AK et al. Effect of Single Dose of Oral Opioid and Nonopioid analgesics on Acute Extremity Pain in the Emergency Department: A Randomized Clinical Trial. JAMA 2017. [JAMA Epub]
3. Hosseininejad SM et al. Efficacy and Safety of Combination Therapy with Ketorolac and Morphine in Patient with Acute Renal Colic; A Triple-Blind Randomized Controlled Clinical Trial. Bull Emerg Trauma 2017. PMCID: PMC5547203
4. Morrison RS et al. Regional Nerve Blocks Improve Pain and Functional Outcomes in Hip Fracture: A Randomized Controlled Trial. J Am Geriatr Soc Cartierpose 2016. PMID: 27787895

For More Thoughts on This Topic Checkout:

• Ryan Radecki at EM Literature of Note: The Acetaminophen/Ibuprofen Ascendancy
• Rory Spiegel at EM Nerd (EMCrit): The Case of the Man Made of Straw Continues

Post Peer Reviewed By: Anand Swaminathan (Twitter: @EMSwami)

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