Morphine VS Ketamine in trauma: the PACKMaN 2025 study
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Effective management of acute pain is a crucial challenge in the pre-hospital emergency setting, especially in trauma patients. A recent study published in The Lancet Regional Health - Europe finally provides solid data to guide our clinical practice in choosing between two main pharmacological options: morphine , which has always been the gold standard in pre-hospital analgesia, and ketamine , an emerging alternative with potentially advantageous pharmacological characteristics.
The PACKMaN (Paramedic analgesia comparing ketamine and morphine in trauma) study represents an important step forward in prehospital analgesia research, being the first randomized, double-blind trial directly comparing these two drugs in the management of severe traumatic pain when administered by ALS (Advanced Life Support) paramedics.
The PACKMaN studio: design and methodology
The study, conducted in the United Kingdom, involved 449 patients with severe acute pain (≥7/10 on the NRS scale) following trauma, randomized to receive ketamine (n=219) or morphine (n=230). The drugs were administered intravenously by paramedics, with a maximum available dose of 30 mg for ketamine and 20 mg for morphine.
Key features of the trial:
Randomized, double-blind, superiority controlled study
Primary outcome: Sum of Pain Intensity Difference (SPID) on arrival at hospital
Average dose administered: 18.8 mg of ketamine vs 12.8 mg of morphine
Average dose per kg: 0.24 mg/kg ketamine vs 0.17 mg/kg morphine
Main results: analgesic efficacy
The most surprising result was that ketamine was not superior to morphine in the primary outcome. The SPID was 3.5 (SD 2.8) for ketamine and 3.4 (SD 3.0) for morphine, with an adjusted mean difference of 0.1 (95% CI -0.4 to 0.6, p=0.74).
However, interesting differences emerge in secondary outcomes:
Patients treated with ketamine were more likely to achieve a "very significant improvement" in pain (>56% reduction).
Ketamine showed a more rapid onset of action but a shorter duration of effect
There was no significant difference in the proportion of patients with final pain score <4/10 (41% ketamine vs 38% morphine)
Safety profile: significant differences
Serious adverse events were rare in both groups (2% ketamine vs 3% morphine), but the side effect profile showed clinically significant differences:
Morphine group : higher incidence of desaturation (16% vs 7%, OR 0.4) and hypotension (10% vs 3%, OR 0.2)
Ketamine group : higher incidence of adverse behavioral reactions (10% vs 1%, OR 8.6)
This difference in safety profile raises an important question: in the context of trauma, where hemodynamic and respiratory instability represent a concrete risk, ketamine could offer a significant advantage despite analgesic equivalence.
What changes in the management of traumatic pain?
From reading the study and the authors' considerations, several key points emerge for our clinical practice:
Ketamine Safety in Non-Anesthetic Hands : Study shows paramedics can safely use ketamine at sub-dissociative doses, without the need for advanced monitoring such as EtCO2. This could pave the way for ketamine to be introduced into standard protocols for paramedics and nurses.
Analgesia still suboptimal : A worrying finding is that approximately two-thirds of patients still arrived in the emergency room with moderate or severe pain, regardless of the drug used. This suggests that there is still considerable room for improvement in prehospital pain management.
Clinical Profile-Based Drug Selection : The authors suggest that desaturation and hypotension pose a greater clinical risk than dissociation in the context of trauma. This would lead to a preference for ketamine in patients at risk for hemodynamic or respiratory instability.
Operational implications : If morphine is as effective as ketamine, prehospital teams could continue to administer it and proceed to hospital, rather than waiting on site for an advanced support team when the goal is purely analgesic (and not sedative).
Specific role in the Emergency Department : Ketamine may have a privileged role in specific subgroups of patients in the ED, especially those with vomiting, hypotension, or hypoxia.
Limitations of the study and considerations
Some limitations to consider when interpreting the results:
The study included only patients able to provide verbal consent, potentially excluding the most severe cases.
No fixed intervals were specified for measuring pain, making it difficult to track trends over time.
No data were collected on the use of non-pharmacological treatments (such as splinting)
Potential selection bias: in the morphine group there were more injuries to the upper limbs, potentially easier to immobilize
The Missing Comparison: Ketamine vs Fentanyl
While the PACKMaN study provides solid data on the ketamine-morphine comparison, it is worth noting that fentanyl —now considered by many to be the gold standard among opioids for trauma analgesia—was not included in the comparison. This is a significant limitation given the evolution of clinical practices.
The PAIN-K (Prehospital Analgesia INvestigation-Ketamine) study published in 2023 in Annals of Emergency Medicine partially filled this gap, comparing ketamine and fentanyl in 210 patients in the prehospital setting. The results showed similar analgesic efficacy between the two drugs, but with different side effect profiles: ketamine showed more psychological/dissociative effects, while fentanyl presented a greater risk of respiratory depression, albeit with a faster onset and lower risk of hypotension compared to morphine.
It would have been extremely interesting to see fentanyl included in the comparison of the PACKMaN study , with the same rigorous methodology and large sample, to provide a more complete picture of the analgesic options available in the prehospital emergency. This tripartite comparison could have better guided clinical choices in light of current practices.
Multimodal analgesia: the synergy between ketamine and opioids
A promising strategy to address the challenge of suboptimal analgesia that emerged from the PACKMaN study is the multimodal approach, which involves the combination of drugs with different mechanisms of action. In particular, the combination of ketamine and opioids is emerging as an attractive option in clinical practice.
In Valle d'Aosta, for example, we routinely use an approach that involves administering an initial dose of ketamine to which an opiate is then added (or vice versa). This practice is supported by several recent studies:
The KOPED (Ketamine-Opioid Pain in the ED, 2022) study demonstrated that the addition of low-dose ketamine (0.15-0.3 mg/kg) to opioid therapy produced greater pain reduction than opioid alone, with a 25% reduction in total opioid consumption and a lower incidence of respiratory adverse events.
Mohammadshahi et al. (2023) highlighted that the ketamine-morphine combination produces more rapid and prolonged analgesia than morphine alone, requiring lower doses of the opioid.
The systematic review by Brinck et al. (2021) concluded that the combined approach offers an “opioid-sparing” effect of 30–50%, maintaining or even improving overall analgesic efficacy.
The advantages of the multimodal approach include:
Exploitation of complementary mechanisms of action (NMDA antagonism and opioid receptor activation)
Reduction of total opioid dosage, with potential reduction of dose-dependent side effects
Faster onset of analgesia
Potential improvement in overall analgesic efficacy
This approach could represent a promising solution to address the problem highlighted by the PACKMaN study, where over 60% of patients arrived at the Emergency Department still with significant pain despite analgesia. A randomized clinical trial specifically comparing the multimodal approach with monotherapy in the prehospital setting would be desirable.
Other strategies to improve overall analgesic efficacy might include more aggressive titration protocols or the systematic integration of nonpharmacological approaches.
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