Elyad Davidson, MD
Professional and Academic Standing
Attending physician, Department of Anesthesiology
Director, Pain Relief Unit, Hadassah-Hebrew University Medical Center
Senior Lecturer, Hebrew University-Hadassah School of Medicine
Member, Board of Directors, Hebrew University Center for Research on Pain
Member, Board of Directors, Israel Pain Association
Chairman, Board of Directors, Acute Pain Section, Israel Society of Anesthesiology
Director, Jerusalem Pain Forum
1. Research in Opioid Pharmacology
Genetic polymorphism of the mu opioid receptor
Opioids, which are among the most widely used drugs for the management of acute and chronic pain,
display wide inter-individual variability in efficacy and side effects. We demonstrated that patients
with a genetic mutation (single nucleotide polymorphism, SNP) for the mu opioid receptor require
higher doses of systemic opioids and achieve higher plasma drug levels when compared with the
normal population, yet they still complain of more pain.28 However, when opioids are administered
spinally, this genetic variability does not influence individual dose requirements. 36 We performed
this study in Hadassah and University of Miami to obtain ethnic heterogeneity. Despite marked ethnic
effects on spinal analgesia, no pharmacogenetic differences were seen for opioids administered via
Safety and enhanced antinociceptive efficacy of methadone
Methadone is a synthetic opioid that is widely used in cases of opioid addiction, but generally not in
acute pain conditions; however, methadone has unique features that could theoretically make it the
opioid of choice in certain pain settings. In Hadassah, the pain service has been using methadone
administered orally, IV, and epidurally for years in patients with acute and chronic pain conditions.
We have demonstrated its safety in hospitalized patients with severe pain,14 and showed enhanced
antinociceptive efficacy of epidural compared with IV methadone in an murine model.37
Given that Hadassah is one of the few medical centers in the world to use epidural methadone for the
management of postoperative pain, we are conducting a large randomized-controlled trial comparing
the effectiveness of methadone to epidural fentanyl or morphine. We have completed a comparison of
postoperative pain levels, opioid side effects, and frequency of chronic post-surgical pain, and the
manuscript is in preparation.
Elyad Davidson MD 2
2. Research in Long-Acting Local Anesthetics
A well-known limitation of currently available local anesthetics is their relatively brief duration of
action. Development of a long-acting local anesthetic would be of great benefit to patients suffering
from acute and chronic pain. We have studied the PK-PD properties of a novel slow-release local
anesthetic. This work began with a PK-PD study in humans of liposomal bupivacaine, which was
developed at Hadassah by Prof Barenholtz.19 This evolved into an industry-sponsored study including
development of a novel proliposomal ropivacaine formulation. We have conducted toxicity studies in
mice and pigs, as well as human PK-PD studies.41 We found that local injection of a high or even
toxic dose of bupivacaine or ropivacaine does not produce high systemic levels in healthy
If these results can be duplicated in the clinical setting, these formulations have the potential to
significantly impact pain management. We are planning clinical studies in patients, together with the
developer of this medication. We still have to demonstrate in an animal model, and later in humans,
an absence of neurotoxic effects with local injection of high-dose proliposomal anesthetics.
3. Research in the Use of Medical Cannabis
Cannabis and nociception
Cannabis has been used in medicine for centuries, for various indications, but substantial progress in
biomedical research to better understand the exogenous and endogenous cannabinoids only began
with discovery of the chemical structure of tetrahydrocannabinol (THC) and additional cannabinoids
in the 1970s. The analgesic effect of cannabinoids has been demonstrated by extensive preclinical
research, but in-depth human studies have been less consistent. Our initial experience with sublingual
THC in patients with chronic nonmalignant pain also showed variable responses;22 however, in our
recent study examining the effect of long-term cannabis treatment on pain and functional outcomes in
one of the largest patient series in the literature, we found that cannabis treatment significantly
improved pain control and sleep, as well as physical, social, and emotional quality-of-life (QOL)
parameters. In addition, patients have reported reduced use of opioids. A manuscript reporting our
findings is currently under review at the JAMA.
Forms of cannabis administration
In collaboration with Prof A. Hoffman of the Hebrew University School of Pharmacy, we conducted
a study examining the bioequivalence of oral administration vs oral spray of a cannabinoid
combination. This trial in healthy human subjects was a PK-PD study using QST, cold pressure tests,
and computerized task performance rapidity tests. We have analyzed the PK data and are now
analyzing the pharmacodynamics data. Based on our preliminary analysis, we are cautiously
optimistic that we may be able to show benefit from a new form of cannabis administration compared
with existing protocols.
Elyad Davidson MD 3
We continue to collect data from about 500 patients who are managed with medical cannabis in the
pain clinic using a combination of questionnaires and medical chart review to assess pain control,
QOL, and medical outcome measures. We hope this research will provide a more complete and
rigorous assessment of the effects of cannabis in humans.
We are planning a national study with a patient population that will include a large proportion of the
16,000 individuals with Ministry of Health approval for the use of medical cannabis in Israel, in
collaboration with Prof O. Bone of Hadassah’s Department of Psychiatric Medicine and Prof Y.
Neumark, Director of the School of Public Health.
Cannabis is consumed recreationally or for medical reasons in 5–15% of the Israeli population;
however, the perioperative effects of cannabis use on anesthesia and surgery are poorly understood.
We have received a grant and preliminary IRB approval to study the effects of a cannabis extract as
anesthetic premedication on perioperative anxiety. and on postoperative pain, nausea, and vomiting.
4. Research to Improve Patient Safety
Regional anesthesia and patient safety
We have demonstrated spinal nerve root inflammation, visualized by MRI, in the difficult to diagnose
situation of transient radiculopathy (TNS).17 Infection or hematoma following epidural anesthesia is a
rare but potentially devastating complication unless diagnosed early. In order to diagnose spinal cord
involvement, the currently recommended imaging test is MRI; however, studies to characterize the
normal appearance of the spine on MRI following uneventful epidural injection have not been
performed. In collaboration with, Prof M. Gomori of the Department of Radiology and Prof D.
Birnbach at the University of Miami, We prospectively evaluated the effects of neuroaxial injections
on appearance of the spinal cord at MRI examination in two prospective studies.21,31 Our group was
the first to determine that there were no significant changes following uneventful epidural injections
performed for the management of lumbar radiculopathy or epidural infusions for labor analgesia. Our
findings from these studies have added significant information that can help to differentiate normal
and pathological MRI findings in cases where complications may occur.
Improving the quality and safety of pain management in a tertiary hospital
Although IV patient-controlled analgesic opioids and epidural analgesia offer improved pain control
for postoperative patients treated in an acute pain service, these modalities also expose patients to
some risk of serious morbidity and even mortality. Root cause analysis, a process for identifying the
underlying cause of an adverse event, has the potential to identify and address risks and problems
with existing pain management protocols, and thereby decrease the risk of specific complications. We
have demonstrated methadone safety in hospitalized patients with severe pain.14 In collaboration with
an international group of researchers we demonstrated the feasibility of international data collection
on postoperative pain management and its feedback effects on quality and safety.34
Elyad Davidson MD 4
In collaboration with Prof M. Brezis and a PhD student, we are conducting an ongoing IRB-approved
prospective study of our acute pain patients treated with IV patient-controlled analgesic opioids and
epidural analgesia. By using root cause analysis methods we hope to identify the causes of individual
adverse events and reduce the risk that these incidents will be repeated.