Adjunctive Pain Management of Renal Colic and Migraines

Background: Renal colic and migraine headaches are common emergency department presentations.  There are a wide range of medications available to treat pain from these disorders including opioids and non-steroidal anti-inflammatory drugs. Opioids have two major issues: dependency and side effects (i.e., apnea, vomiting, etc.). Having multiple medication options is essential in our efforts to reduce the use of opioids as first line therapy for pain control.

Paper: Sadrabad AZ et al. Intravenous Magnesium Sulfate vs. Morphine sulfate in Relieving Renal Colic: A Randomized Clinical Trial. AJEM 2020. PMID: 33071088

 Clinical Question: What is the efficacy of magnesium sulfate in reducing renal colic pain in comparison with morphine sulfate?

What They Did:

• Double-blind randomized clinical trial in renal colic patients in Iran
• Patients randomized to:
  • Magnesium: 10mL NS over 60 sec plus 50mg/kg IV magnesium sulfate (max 2g) with 100cc NS saline over 20min
  • Morphine: 0.1mg/kg IV morphine (max: 5mg) mixed into a 10mL NS syringe over 60s plus 100cc infusion of NS over 20min
• If pain score not reduced by 3, 30mg ketorolac IV was administered as rescue analgesia

Outcomes:

• Primary: Pain score on numerical rating scale (NRS) at 0, 10, and 20 min after infusion
• Secondary:
  • Vomiting
  • Nausea
  • Hypotension (SBP <100mmHg)
  • Apnea
  • Flushing
  • Dizziness
  • Lightheadedness

Inclusion:

• Age 18 to 55 years
• Kidney stone diagnosed through sonographic approach

Exclusion:

• Any history of opium addiction
• Cardiac or renal failure
• Respiratory rate <12BPM
• SBP <100mmHg
• Unwillingness to participate
• Hypersensitivity to morphine or magnesium sulfate
• Inability to understand concept of visual analog scale
• Use of pain killers during 4hr prior to admission
• Renal failure
• Pregnancy and/or lactating

Results:

• 80 eligible patients selected and randomized
• Mean baseline pain score at 0 min before drug administration:
  • Magnesium: 7.88
  • Morphine: 7.93
  • P = 0.88
• Mean pain score at 10min after drug administration:
  • Magnesium: 5.70 (Decrease by 2.18 from baseline)
  • Morphine: 4.88 (Decrease by 3.05 from baseline)
  • P = 0.06
• Mean pain score at 20min after drug administration:
  • Magnesium: 3.20 (Decrease by 4.68 from baseline)
  • Morphine: 3.65 (Decrease by 4.28 from baseline)
  • P = 0.48
• 8 patients (20%) in the magnesium group and 10 patients (25%) in the morphine group failed to respond to treatment in 20 min and required 30mg ketorolac IV as rescue therapy
• No significant difference between groups regarding nausea/vomiting, flushing, and dizziness
• No patients suffered from hemodynamic abnormalities or respiratory depression in either group

Strengths:

• No patients were excluded from the analysis
• All patients received their allocated interventions
• Baseline demographic data were collected by assistants who were unaware of the treatment
• Patients and assessing individuals were blinded to the study
• Baseline characteristics between groups were similar
• No significant difference between baseline scores before medications 

Limitations:

• Appears to be a convenience sample which could bias the results
• Small, single center study that requires validation
• Effectiveness of medications was only tested out to 20 minutes, it is unclear if more rescue analgesia would be required at 30 minutes, 45 minutes, or even 60 minutes
• This was a single agent study without evaluation of combinations of other non-opioid analgesics

Discussion:

• Authors were looking for at least a 3-unit reduction in the VAS pain score over morphine sulfate. Smaller differences would require a larger patient population
• Pain control is typically a combination of medications. It would have been interesting to see ketorolac + magnesium sulfate or morphine in reducing pain.

Author Conclusion: “In this study, we concluded that administration of intravenous 50mg/kg magnesium sulfate could be as effective as morphine in reducing renal colic without any further complications.”

Clinical Take Home Point: In this small, single center RCT magnesium sulfate reduced pain in renal colic at 20 minutes similar to morphine. However, morphine was quicker acting with more pain relief at 10 minutes. This study makes the argument that adding magnesium sulfate to the treatment of renal colic, may help spare opioids as 1^st line agents.

Paper: Meek R et al. Comparing Propofol with Placebo for Early Resolution of Acute Migraine in Adult Emergency Department Patients: A Double-Blind Randomised Controlled Trial. EMA 2020. PMID: 33070469

Clinical Question: Is propofol superior to placebo for the treatment of migraine in adult ED patients?

What They Did:

• Double-blind, randomized controlled clinical trial in Australia
• Patients randomized to:
  • Propofol: (10mg/mL) 4mL followed by up to 5 doses of 2mL, delivered 5min apart (max dose 140mg of propofol)
  • Placebo 20% intralipid (max dose 14mL of 20% intralipid)
• Migraine without aura: Five or previous similar headaches with current headache duration 4 to 72h, with at least two of the following:
  • Unilateral location
  • Pulsating quality
  • Aggravation by or unable to perform routine physical activity
  • Nausea/vomiting
  • Photophobia/phonophobia
• Chronic migraine: Headache presence for 15 or more days per month for more than 3 months
• Medication over-use headache: Use of analgesics for headache on 10 or more days per month for more than 3 months

Outcomes:

• Primary: Headache resolution (15 min after administration of last dose of study drug)
  • This would be 40 min from the initial dose if the max number of doses were given
• Key Secondary Endpoints:
  • Reduction in headache severity by ≥2 points on a numerical rating scale
  • Use of rescue medication
  • Adverse events
  • Headache recurrence

Inclusion:

• Adult patients aged 18 to 65 years
• Acute migraine without aura
• Severity ≥4 on numerical rating scale (NRS)

Exclusion:

• Migraine with aura
• Pregnancy or breast feeding
• Preceding acute (prior to 72hr) or inter-current head trauma
• Initial investigations being undertaken for any non-migraine differential diagnosis
• Altered level of consciousness
• Temperature over 37.9C
• Meeting the definition for chronic migraine or medication over-use headache
• SBP <100mmHg
• Allergy to propofol, intralipid, egg or soy products
• Use within 4hr of any standard anti-migraine medication (including ergotamine, triptans, NSAIDs, beta blockers or neuroleptics including metoclopramide) 

Results:

• 40 patients recruited
  • Initial headache severity was 7 (Range 6 to 8)
  • All pts in the placebo group received the max 14mL of intralipid over 40min
  • 81% of patients in the propofol group received the max dose of140mg over 40 min
• Headache Resolution:
  • Propofol: 24%
  • Placebo: 32%
  • Difference 8%; 95% CI -20 to 36; p = 0.58
• Headache Severity Reduction by ≥2
  • Propofol: 81%
  • Placebo 37%
  • Difference 44%; 95% CI 17 to 71; p = 0.005
• Median Decrease in NRS:
  • Propofol: From 7 to 4 (Range 6 to 8)
  • Placebo: From 7 to 6 (Range 0 to 8)
• 24 patients (60%) received rescue medication. The frequency was similar for propofol and placebo (52% and 68%)
• Two patients in the propofol group developed hypotension (SBP ≈82mmHg) and two patients had excess sedation with GCS of ≈12

Strengths:

• 1^st RCT to compare propofol to placebo in adult ED patients with acute migraine
• Use of intralipid as placebo made it appear with the same consistency and color as propofol
• Used study drug dosing from previously published propofol regimens
• No significant differences in baseline patient characteristics between groups

Limitations:

• Convenience sample of patients with the authors own audit showing many patients were missed during the study period. 96 were eligible to be enrolled but only 43 were consented
• Unblinding likely as clinicians would see response to propofol
• Propofol not compared to standard care for migraines
• Did not take into account time for set up of procedural sedation which will significantly delay administration of propofol
• Follow up information was only obtained in 24 patients (60%) of the study population (12 from each group) meaning that information on headache recurrence was of little use
• Unplanned interim analysis due to flawed sample size calculation

Discussion:

• It may seem crazy to use placebo as a comparator for pain management however, it has been shown that up to 40% of patients report response to placebo [3]
• Headache resolution occurred in at least 80% of patients with propofol from limited previous literature [4]
• Sample size was calculated with the assumption that the primary outcome would be detected for about 36 of 60 patients (24 and 12 for propofol and placebo, respectively). However, the primary outcome was only reported by 11 of the first 40 patients, making the power calculation flawed
• Similar amounts of IV fluid were administered between groups: median volume of 1000mL

Author Conclusion: “Propofol was not superior to placebo for the primary outcome of early headache resolution.  Superiority of propofol for the secondary outcome of headache severity reduction suggests that further research may be warranted.”

Clinical Take Home Point: This small randomized clinical trial does not support the use of propofol over other currently available medications (i.e., Promethazine and metoclopramide).  However, it may be a useful second or third line option in patients where 1^st line agents do not give adequate analgesia but setting up procedural sedation paperwork at some institutions may delay the usefulness of this medication for this indication.

References:

1. Sadrabad AZ et al. Intravenous Magnesium Sulfate vs. Morphine Sulfate in Relieving Renal Colic: A Randomized Clinical Trial. AJEM 2020. PMID: 33071088
2. Meek R et al. Comparing Propofol with Placebo for Early Resolution of Acute Migraine in Adult Emergency Department Patients: A Double-Blind Randomised Controlled Trial. EMA 2020. PMID: 33070469
3. Tfelt-Hansen P et al. Guidelines for Controlled Trials of Drugs in Migraine: Third Edition. A Guide for Investigators. Cephalalgia 2012. PMID: 22384463
4. Krusz JC et al. Intravenous Propofol: Unique Effectiveness in Treating Intractable Migraine. Headache 2000. PMID: 10759925

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

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