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Opioid Alternatives in Acute Severe Pain

Guest post by: Dr. Francis Bakewell

The ED patient in acute severe pain can be a challenge to treat. Even when we prescribe opioids appropriately (which is less often than you think), patient contraindications, side effects, and a poor analgesic response may limit their use. There is lots of new research on opioid alternatives in acute severe pain that ED physicians ought to consider.

Opiods. Food and Drug Administration, America.

Opioid Use and Misuse

·      Opioids mimic our endogenous endorphins, MODULATING the painful stimulus AFTER transmission through our nervous system
·     The range of opioid receptors (mu and delta are the ones we’re mostly concerned with) explain the range of effects, all the way from analgesia to respiratory depression
·      They are predominantly metabolized in the liver and excreted in the kidney (which can limit their use in liver or kidney disease)
·      Many textbooks, including Rosen’s, Harrison’s, and Goodman & Gilman’s, recommend an initial morphine dose of 10mg or 0.1mg/kg IV for acute severe pain (the equivalent suggested hydromorphone dose is 1mg or 0.015mg/kg IV).

·      A landmark study in 1989 demonstrated how bad we are at providing adequate analgesia in the ED: 56% of patients in pain received no analgesia, 42% waited more than 2 hours before receiving any, and 32% received a less than optimum dose1

·     Things may not have changed much since then – a 2010 AJEM study found that while 36% of patients receiving IV opioids remained in severe pain after an initial dose, only 1/3 of them received any subsequent dose titration.2
·       Another study was even more dismal – of 281 ED patients in acute severe pain receiving IV opioids, 95% received less than the recommended textbook dose, and only 2.5% received any subsequent dose titration.3

·       Even AT the recommended dose (morphine 0.1mg/kg IV), our patients may still not get great relief (in one study, only 1/3 of patients receiving the textbook dose got a pain reduction of at least 50% - which is considered the clinical gold standard in judging an effective analgesic effect).4
·    Systematic reviews suggest that the textbook dose is safe, with 0/2095 patients requiring reversal of respiratory depression in one review, and 1/1266 in another.5,6


We still don’t prescribe adequate doses of opioids to patients in acute severe pain (which, generally speaking, are safer than we think). In otherwise healthy patients, we ought to give an appropriate initial dose, and titrate to effect. However, we should also not be surprised if opioids aren’t effective in everyone.

Alternative #1: Ketamine

   There has been a lot research done on the use ketamine as an analgesic, in both the emergency and anesthesia literature.

     Ketamine is primarily an NMDA receptor antagonist, but also a weak mu and kappa agonist, as well as a serotonin, dopamine, and norepinephrine re-uptake inhibitor. This means that it not only MODULATES the painful stimulus after transmission (as the opioids do), but it may actually BLOCK the transmission of the painful impulse in the first place.

Ketamine. Wikicommons

·      It has been studied in a double-blind RCT of 73 trauma patients, with a dose of 0.2mg/kg IV as an adjunct to a standard morphine 0.1mg/kg dose, resulting in less total morphine use (0.149mg/kg vs 0.202 mg/kg), a similar pain reduction, but increased neuropsychological effects (36% vs 3%).7
·      It has also been studied in a double-blind RCT in addition to morphine, at two different doses (0.15mg/kg and 0.3mg/kg). Both ketamine doses achieved a superior absolute pain reduction to morphine alone, although only the higher dose maintained this advantage at the 2 hour mark. Dizziness was reported by 0% and 45% in the low and high dose ketamine groups, respectively, compared to 10% for morphine alone. Dysphoria was reported by 10% and 15% in the two ketamine groups.8
·      A large retrospective case series of 530 patients receiving low-dose ketamine (~0.15mg/kg) may suggest the side effects aren’t actually that prevalent, with only 3.5% of patients having truly psychomimetic or dysphoric reactions (and even fewer requiring any sedation).9


Ketamine for analgesia is experiencing a surge of interest. It appears to allow for greater pain reduction (or at least limits the amounts of opioids used), and is safe. Consider its use in cases where opioids need to be limited, or where pain is refractory. Its biggest drawback seems to be dysphoric and psychomimetic reactions, however these might be reduced by using a low dose (eg. 0.15mg/kg IV over 10 mins, +/- an infusion of 0.03-0.06mg/kg/hr)

Alternative #2: Lidocaine

     A sodium channel blocker that is ubiquitous as a local anesthetic, where it totally blocks nerve transmission. May also have a role as an IV analgesic, although the mechanism is less clear. It is increasingly used in oncologic/palliative settings, as well as in severe chronic and neuropathic pain

Lidocaine. Wikicommons

·    Lidocaine at a dose of 1.5mg/kg vs. morphine 0.1mg/kg was studied in a double-blind RCT of renal colic patients – the lidocaine group had a statistically significant reduction in pain scores, with about 8.3% experiencing transient dizziness and 2.5% experiencing some peri-oral numbness.10
·   Another RCT looked at its use in critical limb ischemia, where a dose of 2mg/kg of lidocaine achieved statistically significant lower pain scores than morphine, without any adverse effects reported.


IV lidocaine has some evidence to suggest its possible use in the ED, however its unclear mechanism and unfamiliar route of administration is likely to make many physicians uncomfortable. Still, its use might be considered in the specific clinical situations studied, and with sufficient monitoring capabilities and buy-in from colleagues in other departments.


Alternative #3: Propofol

      Another drug that we are used to in the ED, although usually for its indication as a procedural sedation/induction agent. It is a hypnotic/amnestic, with most of its effects coming from GABA potentiation, although with some likely sodium channel blocking and endocannabinoid properties. It has primarily been used in the setting of severe/refractory migraine

·      A prospective, non-blinded study in a migraine clinic gave an average dose of 110mg over 20-30 mins to patients, with an astounding 95% reduction in headache on a 10 point VAS, and a recurrence the next day of only 3/77 patients.11
·      A more relatable double-blind RCT from 2014, of 90 ED migraine patients, compared sumatriptan 6mg SC (the migraine treatment with the strongest recommendation from the Canadian Headache Society) with propofol 30-40mg bolus, followed by 10-20mg boluses until a RASS of 3-4 was achieved (essentially procedural sedation). All patients achieved similarly remarkable pain reductions, although the propofol group achieved it quicker, with a much lower rate of recurrence in 24 hours (17% vs 55%).12


While it was weakly recommended AGAINST in the most recent Canadian Headache Society guidelines13 (primarily due to concerns about its ineffectiveness and side effects of drowsiness and slurred speech), propofol is a drug we are eminently familiar with in the ED, and is potentially worth a try for the patient who is refractory to standard migraine treatments.

Dr. Francis Bakewell is a fourth-year Emergency Medicine resident at the University of Ottawa, and a MHSc. candidate in Bioethics through the Joint Centre for Bioethics at the University of Toronto.

Edited by Dr. Shahbaz Syed, 4th year Emergency Medicine resident, University of Ottawa


1. Wilson J and Pendleton J. Oligoanalgesia in the emergency department. AJEM. 1989; 7(6): 620-623
2. O’Connor et al. Intravenous opioid dosing and outcomes in emergency patients: a prospective cohort analysis. AJEM. 2010; 28: 1041-1050
3. Bijur et al. Dosing and titration of intravenous opioid analgesics administered to ED patients in acute severe pain. AJEM. 2012; 30: 1241-1244
4. Bijur et al. Intravenous morphine at 0.1mg/kg is not effective for controlling severe acute pain in the majority of patients. Annals Emer Med. 2005; 46(4): 362-367
5. Patanwala et al. Intravenous opioids for severe acute pain in the emergency department. Ann Pharmacother. 2010; 44: 1800-1809
6. Niemi-Murola et al. Parenteral opioids in emergency medicine – a systematic review of efficacy and safety. Scand Jour Pain. 2011; 2: 187-194

7. Galinski et al. Management of severe acute pain in emergency settings: ketamine reduces morphine consumption. AJEM. 2007; 25: 385-390
8. Beaudoin et al. Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial. Acad Emerg Med 2014; 21: 1194-1202
9. Ahern et al. The first 500: initial experience with widespread use of low-dose ketamine for acute pain management in the ED. AJEM. 2015; 33: 197-201
10. Soleimanpour et al. Effectiveness of intravenous lidocaine versus intravenous morphine for patients with renal colic in the emergency department. BMC Urology. 2012; 12:13
11. Krusz et al. Intravenous propofol: unique effectiveness in treating intractable migraine. Headache. 2000; 40: 224-230
12. Moshtaghion et al. The efficacy of propofol vs. subcutaneous sumatriptan for treatment of acute migraine headaches in the emergency department: a double-blinded clinical trial. Pain Practice. 2014 Jul 12. doi: 10.1111/papr.12230. [Epub ahead of print]

13. Orr et al. Canadian Headache Society systematic review and recommendations on the treatment of migraine pain in emergency settings. Cephalalgia. 2015; 35(3): 271-284


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