Pain Profiles: Ketorolac and Morphine in Renal Colic

Written by: David Cisewski, MD (@PainProfiles – EM Resident Physician, Icahn School of Medicine at Mount Sinai) // Edited by: Manpreet Singh, MD (@MPrizzleER), Alex Koyfman, MD (@EMHighAK), and Brit Long, MD (@long_brit)

Today’s post in the Pain Profiles series by Dr. David Cisewski evaluates the intranasal route for analgesics.

Efficacy and Safety of Combination Therapy with Ketorolac and Morphine in Patient with Acute Renal Colic; A Triple-Blind Randomized Controlled Clinical Trial

Hosseininejad SM, Amini Ahidashti H, Bozorgi F, Goli Khatir I, Montazar SH, Jahanian F, Amooei Khanabbasi M. 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;5(3):165-170.

One-Liner

Combination of morphine plus ketorolac is more effective at short-term pain reduction than either agent alone in the treatment of acute renal colic.

Study Characteristics

• Clinical question: Is the combination of opioid (morphine) and NSAIDs (ketorolac) more effective at at reducing pain from acute renal colic than either agent alone? 
• Design: ED-based, Triple blinded, randomized controlled trial.
• Setting: Emam Khomeini hospital, a tertiary general hospital associated with Mazandaran University, Iran.
• Patient/Population: 300 patients presenting age 18-55 years old, with acute renal colic, VAS 4-10 cm, without peritoneal signs.  Patients were excluded if they were pregnant, breastfeeding, history of renal transplant, peptic ulcers, cardiovascular disease, ACE-inhibitor/angiotensin receptor blocker use, or history of opioid use / methadone abuse.
• Intervention: Patients randomized into three arms to receive either 30 mg ketorolac, 0.1 mg morphine, or the combination of 30 mg ketorolac + 0.1 mg/kg morphine.  The single-treatment regimens also received a normal saline intravenous placebo.   Visual analog scale (VAS) measurements were taken at baseline, 20 min, and 40 min to assess pain reduction.  Need for rescue medication (VAS score > 4 cm received addition 0.05 mg/kg morphine) and side effects were also measured in each group.
• Outcome: Baseline pain score were similar for morphine (8.38), ketorolac (8.34), morphine/ketorolac (8.36). Pain score were not statistically different at 20 min (morphine – 4.57, ketorolac – 5.32, morphine/ketorolac – 4.71) but a statistical difference was noted at 40 minutes with the combination analgesia resulting in a superior pain reduction that each single-regimen treatment (morphine – 3.66, ketorolac – 3.68, morphine/ketorolac – 3.01; p = 0.012).  The combination regimen also resulted in less requirement for rescue analgesia  (morphine – 20%, ketorolac – 24%, morphine/ketorolac – 16%; p = 0.043). Each group resulted in similar side effect profile.
• Conclusion: The combination of morphine plus ketorolac is more effective at short-term pain reduction  of acute renal colic than either agent alone.

The Upshot

As opposed to a comparison of opioids versus other analgesics, this study provided a unique look at the synergistic effects of opioid + NSAID analgesia.  Any study that demonstrates an ability to combine medications in order to maximize pain relief while minimize side effects deserves promotion. However, the results of this study were not without caveats as so eloquently stated by Dr. Sergey Motov below.

Should we use a combination of analgesics in the ED to manage pain of renal colic origin?

“A push for mechanistic (neurobiological) approach to pain management, has allowed EM clinicians to broadly utilize the combinations of analgesics of different classes that act on the different target sites with a hope of providing greater pain relief with lesser degree of side effects. Renal colic represents one of the most painful syndromes encountered in the ED and, based on the literature and personal experience, single analgesic (opioid or NSAID) fails to provide acceptable pain relief in about 50% of patients. Thus, it seems intuitive to use a combination of above mentioned classes of analgesics, so the percentage of patients experiencing pain relief from renal colic will be much higher. But does this combination work in clinical practice? 

Hosseininejad and colleagues conducted a triple blind randomized trial comparing analgesic efficacy of so-called “balanced analgesia” with a combination of intravenous ketorolac and morphine to either agents alone to manage renal colic pain in the ED. Based on the pre-determined significant statistical difference of 5% between groups, authors concluded that a combination therapy provided grater pain relief at 40 min than either morphine or ketorolac alone. But I would like to point few details out. 

First of all, strict upper age limit to 55 and extensive list of exclusion criteria may not be generalizable to the rest of the population in the world.

Second, the 5% statistical difference between groups with respect to analgesic response is clinically useless by any stretch of imagination. Does is really matter from clinical perspective if patients pain improved by 5.3 or 4.8 points at 40 min?   Does a half-point translate into a meaningful pain relief? The answers are no. I struggle to accept a clinically acceptable and statistically proven difference of 1.3 (13 mm) in pain score between groups ( Bijur 2003, Holdgate 2003) as truly meaningful difference in real life, and after reading this paper, am I to really believe that half-a-point is that significant? I would have rather liked to see how many patients in each group achieved 50% or greater change in pain score at 20 and 40 min from the baseline.

Lastly, I am always fascinated with a stipulation of using a half-dose of rescue medication after a full dose of the very same medication (in this study morphine at 0.1 mg/kg) did not achieve the desired level of analgesia. How is the half dose going to help?

I am a big proponent of combining analgesics form different classes in believe that analgesic synergy between them will result in greater pain relief. I do believe that combinations of NSAID and opioid, or NSAID and non-opioid frequently result in better analgesia for patients suffering from renal colic. But not always. In this trial, the combination therapy of intravenous ketorolac and morphine did not result in superior analgesia in comparison to ketorolac and morphine administered alone. But, the combo therapy required less rescue analgesia than either morphine or ketorolac.”

– Sergey Motov, MD

This post is sponsored by www.ERdocFinder.com, a supporter of FOAM and medical education, who with their sponsorship are making FOAM material more accessible to emergency physicians around the world.

Reference:

Bijur PE, Latimer CT, Gallagher EJ. Validation of a verbally administered numerical rating scale of acute pain for use in the emergency department. Acad Emerg Med. 2003;10:390-392.

Holdgate A, Asha S, Craig J, et al. Comparison of a verbal numeric rating scale with the visual analogue scale for the measurement of acute pain. Emerg Med Australas. 2003;15:441-446.

Further Reading

• Soleimanpour H et al. Effectiveness of Intravenous Lidocaine Versus Intravenous Morphine for Patients with Renal Colic in the Emergency Department. BMC Urology 2012; 12(13): 1 – 5. PMCID: PMC3508963
• Firouzian A et al. Does Lidocaine as an Adjuvant to Morphine Improve Pain Relief in Patients Presenting to the ED with Acute Renal Colic? A Double-Blind, Randomized Controlled Trial. Am J Emerg Med 2016; 34(3): 443 – 8. PMID: 26704774
• Salim Rezaie at REBELEM –IV Lidocaine for Renal Colic: Another Opioid Sparing Option?
• Alexis LaPietra, DO at ALiEM –Intravenous Lidocaine for Renal Colic
• emDocs – Nephrolithiasis: Diagnosis and Management in the ED