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The Academy of Aid-in-Dying Medicine (Academy) maintains a database of voluntary clinician case reports that includes detailed information, including medications and dosages, patient factors associated with longer deaths, and time to death after taking the medications.

Over the past two years, some attending/prescribing clinicians began using a higher-dose version of the standard DDMAPh protocol in an effort to reduce prolonged deaths. The high-dose regimen consists of a doubling of diazepam (from 1 to 2 grams) and phenobarbital (from 5 to 10 grams); the amounts of digoxin (100mg), morphine (15g), and amitriptyline (8g) remain the same. Some prescribed the high-dose regimen for all patients; others reserved it for patients with risk factors associated with longer times to death; many did not use it at all. In the absence of guidance, individual clinicians made their own choices.

In the accompanying Journal of Aid-in-Dying Medicine article, “Dose Increase in Medical Aid in Dying: An Outcomes Comparison of Higher- and Usual-Dose Prescriptions,” the authors analyzed the Academy data to compare outcomes (time to death) with usual-dose and high-dose DDMAPh.

In an all-patients cohort, the high-dose regimen was not associated with shorter times to death. Average time to death was actually longer in the high-dose group, a seeming paradox explained in the recommendations below.

Among a subgroup of patients with one or more risk factors associated with longer deaths, however, high-dose DDMAPh was associated with a 16.8% shorter mean time to death and a 5.4% shorter median time to death. The greater difference in the mean than in the median suggests that the benefit may be concentrated among the longest deaths. Deaths exceeding 20 hours occurred in 7 of 313 patients receiving usual-dose DDMAPh and 1 of 211 receiving high-dose DDMAPh—a 77% relative difference.

These findings (p = 0.85) did not reach statistical significance, and the eight >20-hour deaths provide only a small basis for estimating the outlier effect. Chance remains a plausible explanation. The authors also acknowledged the limitations of a retrospective study, and a voluntary reporting system that might include selection bias. They concluded: “The available evidence is insufficient to support a formal recommendation for the higher-dose regimen.” The data suggest a possible benefit; they do not establish one.

So what’s a clinician to do? That’s where the Academy can be helpful. A scientific article must describe what the data can support. A clinical organization must also help clinicians make reasonable decisions when the evidence is incomplete — where limited data meets clinical realities.

Aid-in-dying medicine remains a young field. The institutions that ordinarily conduct large prospective pharmacology studies have generally not participated in aid-in-dying research — for a variety of reasons including stigma about the practice. And they are unlikely to do so for many years. Meanwhile, clinicians are caring for aid-in-dying patients every day in jurisdictions that represent 33% of the U.S. population. Clinicians and patients cannot always wait for ideal studies; they need carefully qualified guidance based on the best evidence available.

The Academy convened a six-member clinical advisory group composed of the three study authors and three active attending/prescribing clinicians. The group reviewed the evidence and considered whether a pragmatic recommendation was warranted. They considered:

• Is high-dose DDMAPh potentially helpful? If so, for which patients?
• Is high-dose DDMAPh potentially harmful? What other disadvantages might it impose?
• How frequent and consequential are prolonged deaths for patients, families, and clinicians?

Should high-dose DDMAPh be used for all patients?

No. The Academy does not recommend routine use of high-dose DDMAPh for all aid-in-dying patients.

In the all-patients cohort — patients with and without risk factors associated with longer deaths — high-dose DDMAPh showed no improvement in time to death. Mean time to death was actually longer with the high-dose regimen than with the usual dose. This apparent paradox likely reflects clinicians’ preferential use of high-dose DDMAPh in patients already expected to have longer deaths, particularly those with opioid tolerance or gastrointestinal absorption concerns. This skewed the all-patient high-dose results toward longer times to death and does not show that the higher dose caused longer deaths.

High-dose DDMAPh is also more expensive and requires a larger volume of liquid suspension, potentially decreasing patients’ ease of ingestion (by oral or non-oral routes). So while it might be tempting to standardize all DDMAPh pharmacology to a single high-dose formula, the Academy does not recommend that high-dose DDMAPh be used for all patients.

Should high-dose DDMAPh be used for selected patients with one or more risk factors associated with longer deaths?

Yes. The Academy recommends consideration of high-dose DDMAPh for patients with one or more risk factors associated with prolonged death. With careful patient selection and individualized clinical judgment,

This is a pragmatic recommendation, not a claim that the study proved efficacy. It rests on a favorable but statistically nonsignificant trend, the possibility that the benefit is concentrated in rare prolonged-death outliers. The Academy is taking into account that the data showed a positive trend, and better-powered studies are unlikely to arrive for many years.

The six members of this Academy clinical advisory group unanimously agreed that deaths in the >10-hour range have a strong potential to be stressful for families and clinicians maintaining the bedside vigil (even considering that the patients are uniformly unconscious and comfortable). One member observed:

“In an emerging field of medicine, treatment decisions sometimes must be made on the basis of lower-strength evidence. Extreme outliers have an outsized impact on families. If an approach may help and is not harmful, we should offer carefully qualified guidance while continuing to collect the data needed to test it.”

Conclusions and recommendations:

• The Academy of Aid-in-Dying Medicine does not recommend routine use of high-dose DDMAPh for all patients.
• The Academy recommends that clinicians consider high-dose DDMAPh for patients with one or more risk factors associated with longer deaths.
• The recommendations are provisional and should be revisited as additional data become available.

These recommendations provide general clinical guidance, not a treatment directive for any individual patient. Clinicians must assess each patient and weigh potential risks, benefits, and other clinical considerations through shared decision-making.

The Academy strongly urges clinicians using any aid-in-dying formula to submit outcome data at https://link.aadm.org/DataReports. Continued reporting will allow the Academy to evaluate and update these recommendations.