Sergey Motov discusses his new study and the approach to managing pain in this challenging population.
Nicholas Genes: Hello Sergey! Great to talk with you again, and congratulations on the new publication. We know the problem of oligoanalgesia in the elderly – they may be unable to advocate for themselves, may have varying degrees of impaired metabolism and doctors are reluctant to dose pain medications at standard doses and intervals.
But when I first saw your new GERIKET trial, I wondered why ketamine? Why not work on better titrating the dose of morphine, or looking into new forms of safe, familiar drugs like IV APAP?
Sergey Motov: Hello Nick! It is great indeed to be back to EPM and to chat with you about ED Pain Management. As you are well-aware, pain management of elderly patients in the ED is extremely challenging and despite the significant advancements of our analgesic armamentarium, it remains suboptimal. Age-related changes in drug absorption, metabolism and clearance, multiple and at times dangerous drug-drug interactions, and underlying renal and hepatic insufficiency put elderly patients at increased risks of side effects and treatment failures related to commonly used analgesic classes such as opioids and NSAIDs.
The results of so-called geriatric “opiophobia” are two-fold. First, the elderly patients are less likely to receive opioid analgesics (oral or parenteral) in the ED and on discharge in comparison to their younger counterparts. Second, when opioids are prescribed, elderly patients receive them in suboptimal dosages. To make an issue of opioids and geriatric patients even worse, even with optimal doses, some of the opioid-related side effects such as hypotension, lethargy, respiratory depression and at times delirium, are associated with significant morbidity of the elderly.
NSAIDs (with exception of topical forms) are not really suitable for elderly due to undesirable side effects profile (worsening renal failure, acute GI hemorrhage, worsening CHF, etc.) and lack of titratability.
Genes: So what do you have left? IV Acetaminophen?
Motov: Intravenous Acetaminophen (APAP) might be an option for elderly patient who are unable to tolerate/or have contraindications to opioids and NSAIDs, and unable to tolerate PO acetaminophen. However, the intravenous acetaminophen should be used in the ED on a case-by-case basis due to insane acquisition cost, lack of titratability, and the often-neglected interaction with warfarin.
There are reports that with APAP doses ranging from 1.3g to 4g per day, the INR goes up by 1 or more. A toxic metabolite of APAP called NAPQI can inhibit the Vitamin K cycle at several points, so INR monitoring on Tylenol is important. Another fact about IV APAP is that is very effective for fever control, but when it comes to moderate-to-severe pain in the ED, its analgesic efficacy as a single agent is modest at most.
ED clinicians need to explore alternatives to opioids and NSAIDs in the ED that can provide comparable to or even better pain relief but with lower rates of serious side effects.
Genes: So you turned to ketamine.
Motov: Sub-dissociative-dose ketamine seemed like an option worth studying, yes.
Ketamine is a non-competitive NMDA/glutamate receptor complex antagonist that reduces pain by decreasing central sensitization, “wind-up” phenomenon, and hyperalgesia at the level of the spinal cord (dorsal ganglion) and central nervous system. Ketamine given in a sub-dissociative dosing range (0.1-0.3 mg/kg) results in anti-hyperalgesia, anti-allodynia and anti-tolerance, which makes ketamine a useful analgesic for managing a variety of acute and chronic painful conditions.
Evidence from EM literature clearly supports sub-dissociative dose ketamine (SDK)analgesia in patients with acute traumatic and non-traumatic pain, chronic and cancer pain, opioid-tolerant pain and opioid-induced hyperalgesic states. However, the upper age limit of the ED patients in majority of the studies (if not all) studies was 65.
Genes: And in GERIKET you were able to look at elderly ED patients…
Motov: Yes, we did. We enrolled patients older than 65 years of age with patients in the morphine and ketamine arms with an average age of just over 77. About a quarter of patients were male. We were looking at patients who presented with acute pain (abdominal, flank, back or MSK) with pain intensity level at or greater than 5 on the 11-point numerical pain rating scale.
Genes: And how well did sub-dissociative ketamine work in this population?
Motov: The change in mean pain score at 30 minutes was not significantly different between sub-dissociative ketamine group and morphine group: 4.8 points vs. 4.0 points. Similarly, there was no statistical difference in change of pain score between two groups at 60 minutes, 90 minutes or 120 minutes. However, at the 15-minute mark, a group receiving sub-dissociative dose ketamine had greater reduction in pain from the baseline in comparison to morphine group: 6 points vs. 3.4 points. Lastly, more patients in sub-dissociative dose ketamine group reported a complete resolution of pain: 52% of patients vs. 17% of patients in morphine group.
However, while pain relief at 15 minutes was greater with SDK than with morphine, the effectiveness of subdissociative ketamine was overshadowed by the incredibly high rates of predominantly psychoperceptual adverse effects at 15 minutes and 30 minutes: 87% and 73% of patients, respectively.
Genes: Well, that’s considerable. But of the 60 patients in this trial (30 in each arm) there were no really bad outcomes — no hypotension or bradypnea with morphine, for instance. Significantly more ketamine patients reported dizziness. One morphine patient required oxygen briefly, but two ketamine patients needed oxygen. Three morphine patients needed zofran, but five ketamine patients needed it. So… would it be fair to say that this study shows the safety and efficacy of morphine, when properly dosed, in older patients? Would you blame an EP who looked at this paper and said, “I’d much rather use morphine as first-line, instead of ketamine”
Motov: You are correct! When properly dosed, morphine for the most part is safe and effective. I would never blame an EP for giving morphine to elderly patients in appropriate dosing regimens and titratable fashion when indicated. And resort to sub-dissociative dose ketamine when opioids are contraindicated or undesirable. The issue is that our study was severely underpowered to truly evaluate and compare safety. So, we need to be honest and at the same time cautious when interpreting results.
Genes: When we spoke before, you mentioned that you’ve worked with your ED’s nurses to develop a short-infusion protocol for ketamine – over 15 minutes, either by adjusting the IV drip rate or using a pre-programmed pump. Prior research has shown this minimizes the disorientation associated with ketamine, without sacrificing pain relief.
I thought it was interesting in the paper that you administered morphine over a 15-minute infusion, as well. Of course, that’s good science (blinding!), but you wrote that slowly infusing morphine results in less nausea and lightheadedness. Do you routinely administer morphine this way? Is this something I should try, for my patients who ask for dilaudid, because morphine makes them nauseous?
Motov: I routinely administer morphine and fentanyl via short (over 10 minutes) infusion with a dosing at of greater than 8 mg of morphine or at or greater than 75 mcg of fentanyl. The rates of side effects related to opioids are directly proportional to a dose and the rate (speed) of infusion. Morphine, for instance, when administered via intravenous push, causes more rapid saturation of mu-receptors in chemoreceptor trigger zone in the medulla that leads to nausea and vomiting and rapid histamine release with resultant hypotension. Similarly, intravenous push of hydromorphone causes prominent euphoria and respiratory depression. Thus, extending the infusion to 10 to 15 minutes will preserve analgesic efficacy, but will result in better patient’s tolerance of opioids and lesser severity of adverse effect.
Genes: So based on this new research, and your prior research, reading and experience, what’s your approach to the elderly ED patient with say undifferentiated abdominal pain?
Motov: Patient-specific approach with emphasis on hemodynamic status, co-morbidities and drug-drug interactions will dictate the choice of the initial analgesic regimen. In an elderly patient with severe undifferentiated abdominal pain and no contra-indications to opioids, intravenous morphine at 0.05 mg/kg weight-bases dose, or 3-4 mg fixed dose is a reasonable initial approach with a re-assessment at 20 to 30 minutes and dose titration as needed. Alternatively, sub-dissociative ketamine at 0.1-0.15 mg/kg over 30 minutes either as a single agent or as an adjunct to morphine might be considered. Lastly, on individual case bases, and if patient is strictly NPO, consider IV Acetaminophen as an adjunct to opioids or ketamine. But remember to make sure you check the INR if the patient is on warfarin!