This is the fourth in a series of blog posts on new research in emergency toxicology. The last post was about toxic alcohol ingestion and can be found here. We deal with all sorts of poisons here in Virchester, so be prepared for anything.
The majority of patients come to hospital because they are in pain. Giving analgesia is one thing that we can do in the emergency department (ED) to relieve their suffering. Sadly, under-treatment of pain – ‘oligoanalgesia’ – is widespread in our practice. Women for example, are substantially less likely to receive adequate analgesia in ED, as are patients from racial / ethnic minority backgrounds.
Another group at risk of under-treatment is patients who are opioid-dependent. Users of illicit opioids – such as heroin – seem to have it particularly rough. Research has shown that they tend to receive less analgesia in the ED than other patients – even if there is an obvious source of pain, such as a fracture. I have personally seen patients with horrible injection-site abscesses being told to “cope” on a low dose of codeine.
Why does this happen? One contributing factor is the stigma associated with illicit drugs, and the accompanying belief that users are “drug-seeking” when they present to ED. Another is a failure to appreciate the physiological changes associated with opioid dependence, which include predisposition to acute pain – opioid hyperalgesia – and “tolerance” to painkillers at the doses we typically prescribe.
The ideal solution to this problem would be an analgesic agent that is effective in opioid users and perceived by ED clinicians to be “appropriate” for them. One option is ketamine. A recent meta-analysis has shown that sub-dissociative dose ketamine (~0.1-0.3 mg/kg) has comparable efficacy to morphine for medical and surgical pain. It can be given via several routes, and on St Emlyn’s we have looked at studies using nebulised, intranasal, and intravenous preparations.
What we do not yet know is whether ketamine works as well in opioid-dependent patients. Helpfully, Academic Emergency Medicine published a trial on this subject a few months ago. The aim of the study was to establish whether patients receiving morphine for acute pain benefit from adjunctive ketamine – and whether this benefit extends to opioid users.
Abstract
Background: Pain is a common complaint among patients presenting to the emergency department (ED), yet pain treatment is frequently suboptimal. The aim of this study was to determine the effectiveness of low-dose ketamine (LDK) as an adjunct to morphine versus morphine alone for treatment of acute pain among ED patients with and without current opioid use.
Galili S, Bech B, Kirkegaard H, Ahrensberg J, Nikolajsen L. Low‐dose ketamine as an adjunct to morphine: A randomized controlled trial among patients with and without current opioid use. Academic Emergency Medicine. 2024 Oct.
Research design and methods: Adult patients presenting with acute pain of ≥5 on a numeric rating scale (0–10) who were deemed by their treating ED physician to require intravenous opioids were randomized to receive either 0.1 mg/kg ketamine (treatment group) or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain was measured at baseline (T0) and 10, 20, 30, 45, 60, and 120 min after randomization. The primary outcome was pain reduction from T0 to T10. Secondary outcomes included pain intensity over 120 min, need of rescue opioids, side effects, and patient and provider satisfaction.
Results: A total of 116 patients were included from May 2022 to August 2023. Median (IQR) age was 51 (36.5–67) years; 58% were male and 36% had current opioid use. Pain reduction from T0 to T10 was greater in the LDK group (4 [IQR 3–6]) compared to the placebo group (1 [IQR 0–2]; p = 0.001). Pain intensity was lower in the LDK group at T10, T20, and T30, compared to the placebo group. There was a higher risk of nausea, vomiting, and dissociation in the LDK group during the first 10 min.
Conclusions: LDK may be effective as an adjunct analgesic to morphine for short-term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use.
What was the study design?
This was a randomised controlled trial conducted at an academic centre in Denmark between 2022 and 2023.
Can you tell me about the patients?
The researchers aimed to recruit adults (>18 years) presenting to the ED with acute pain. This was defined as pain that was 5/10 or greater in severity and deemed to require treatment with intravenous opioids in the view of the treating physician.
There were many exclusion criteria for the trial, including severe psychiatric illness, untreated glaucoma, severe hypertension (SBP > 180mmHg), and known adverse reactions to ketamine. Patients were also excluded if they were intoxicated on arrival to ED, although the authors do not describe how this was assessed.
In total, 900 patients were screened and 116 recruited into the trial. The majority were middle-aged, with a slight (57%) female preponderance. The average pain level at baseline was severe (8/10) and felt most commonly in the abdomen (43.9%), extremities (22.4%), and back (18%).
Thirty-one patients disclosed current opioid use. This was defined as ‘daily consumption of any type of opioid for a minimum of 7 days,’ although it is not specified by the authors whether this refers to prescribed medications, illicit substances, or both. The published manuscript does state that ‘[d]oses were confirmed in the electronic patient record’ – which would suggest to me that these patients were not getting their drugs from the street.
What was given to them?
All patients in the trial received a dose of intravenous morphine. Opioid-naïve participants received a 0.05-0.1 mg/kg bolus. Opioid users received either 15% of their daily dose or 0.05-0.1 mg/kg, whichever was higher.
The intervention group received an additional bolus of intravenous ketamine (0.1 mg/kg) immediately after their morphine. The control group received the same volume of saline as a placebo.
Both medications were prepared by a nurse unaffiliated with the study. Patients, treating clinicians, researchers, and statisticians were unaware of allocation.
After ten minutes, trial participants could have rescue analgesia if needed. This could be more morphine, a nerve block, paracetamol, or an NSAID.
What outcome measures were used?
The primary outcome was reduction in subjective pain at the ten-minute mark.
There were numerous secondary outcomes used, including adverse drug reactions, need for rescue opioids, and subjective pain in the two hours post-intervention.
What were the main results?
Overall, superior pain reduction was found in the adjunctive ketamine group (-4; IQR 3-6) compared to the control group (-1; IQR 0-2). The effect of ketamine was accentuated (-5; IQR 3-6) in opioid users.
Pain intensity remained lower for thirty minutes in patients given ketamine. After this, no significant differences were observed between groups, although the patients who received a placebo used more rescue opioids: 50 total doses as opposed to 43, which amounted to 143mg more once converted to oral morphine equivalent.
There were more short-term adverse reactions seen in the patients given ketamine. These included dizziness and dissociative experiences. At twenty minutes post-administration, no differences were observed between groups for these side-effects. Similar amounts of nausea and vomiting were seen in both trial arms throughout the monitoring period.
What should we take away from this study?
This trial supports ongoing efforts to “bridge” the findings of prior ketamine studies to patients who use opioids. Clearly, they need to be included in our research! Before reading this paper, I might have assumed that opioid users would be too tolerant for low doses of ketamine (0.1-0.3 mg/kg) to exert much of a potentiating effect. This appears not to be the case.
The key limitation to this trial, in my eyes, is the exclusion of patients with active intoxication or a history of major psychiatric illness. Many individuals who abuse opioids struggle with mental health problems, and it is typical for them to self-medicate pain with drugs or alcohol before coming to ED. These exclusion criteria may have prevented the patients I am most interested in – heroin users – from participating.
The other drawback worth discussing is the acuity of the patients in this trial. Their baseline pain averaged to 8/10, and they were believed by their clinicians to require intravenous opioids. These, to me, are patients in crisis, who represent a minority of the patients we prescribe opioids for in ED. I would have been curious to see what ketamine did for fives, sixes, and sevens. We know that all under-treated pain contributes to suffering in ED – even the so-called “moderate” cases.
Should this study change our practice?
Yes. This trial demonstrates that ketamine is a valid option for opioid users who present to ED with acute pain. Participants reported a significant drop in pain after ketamine, and used less opioid afterwards. The effect lasted for at least forty-five minutes, which, although not perfect, at least shows the value of ketamine for the initial crisis. It is likely to be more helpful to opioid-tolerant patients than further boluses of morphine.
I would like to see future pain studies adapt their enrolment process to illicit opioid users. I have recruited heroin users to trials here in Virchester, and although there are barriers – particularly around follow-up – they are by no means insurmountable.
Greg Yates
Low-dose ketamine has been very helpful in my patients who are on chronic opioid therapy.