A presentation by Joseph Cravero at the 2017 meeting of the Scandinavian Society of Anaestesiology and Intensive Care Medicine.
All available content from SSAI2017: https://scanfoam.org/ssai2017/
Delivered in collaboration between scanFOAM, SSAI & SFAI.
3. Objectives of the Lecture
1. To appraise advantages and
limitations of existing local
anesthetics
2. To assess how new local
anesthetics might change our
clinical practice in the near future
5. Opioids are Partially Effective, but
with Side-Effects and Risks
• Somnolence, Mental Clouding
• Respiratory Depression
• Nausea and GI Dysfunction
• Addiction
19. Duration is too short.
• Bupivacaine and ropivacaine
average durations: 10 hours with
peripheral blocks
• Pain lasts for several days after
major surgery.
• Catheters are “high-maintenance”.
20. • CNS -> seizures
• Cardiac -> arrhythmia,
cardiac arrest
• Exacerbated by hypoxemia and
acidosis.
• Resuscitation is difficult.
Systemic Toxicity of Local
Anesthetics
25. Bupivacaine in Lipid Depot Foam (Exparel®)
• FDA approval for wound infiltration for
postoperative analgesia
• Not sufficiently dense for surgical
anesthesia
• Positive clinical trials mostly against
placebo.
• > 24 hours of analgesia vs. placebo
• very small effect size from 24 – 72 hours
26. Bupivacaine in Lipid Depot Foam (Exparel®)
• Most trials against standard aqueous
ropivacaine or bupivacaine have not
shown superiority; in some trials, Exparel
was inferior to active control.
• FDA initially deferred approval for nerve
blockade, re-review in progress
• very rapid increase in sales in U.S.
• not approved in Europe
27. Bupivacaine in Lipid Depot:
Exparel® – Clinical Trials and Use
• Pivotal trials: hemorrhoids, bunions,
breast reduction
• PK shows safe blood concentrations
with bupivacaine doses from 150 – 600
mg
• Higher doses showed some reductions
in pain scores or opioid use compared to
controls.
28. Pain Scores with Movement After Wound
Infiltration for Knee Arthroplasty
29. Site 1 Sodium Channel Blockers
Derived from Marine Toxins
• Puffer fish
• Red-tide on a seacoast
30. Site 1 sodium channel blockers
• e.g. tetrodotoxin, saxitoxin
• Very high potency on isolated
nerve
• Minimal local neurotoxicity
• Minimal effect on cardiac muscle
• Minimal CNS entry
33. Combinations of site-1 blockers with
bupivacaine show synergistic prolongation
of sensory blockade
(Kohane et al Anesthesiology 1998)
34. Epinephrine dramatically increases the
potency of site 1 toxins in nerve blockade.
Note: Epi reduces ED50 for half-
maximal sensory block by 4-fold
34
39. Clinical Trials in Chile
• Phase 1 - skin infiltration in volunteers
– NeoSTX: more prolonged skin numbness
compared to bupivacaine.
– NeoSTX + bupivacaine: more prolonged
numbness than NeoSTX alone or
bupivacaine alone
– NeoSTX was well tolerated- no local or
systemic toxicities.
Rodriguez-Navarro et al Anesthesiology 2007, Neurotox res.
2009
40. • 137 patients undergoing laparoscopic
cholecystectomy, general anesthesia
• Double blind comparison to bupivacaine
• Infiltration of incisions
• Primary outcomes: pain scores at 12 and
24 hours
• Secondary outcomes: global recovery
scale, safety
Phase 2 RCT Superiority Trial
Rodriguez-Navarro et al. Regional Anesthesia and Pain Medicine. 2011;
36:103-109
41. Compared to Bupivacaine patients,
NeoSTX patients had lower pain
scores, and were more likely to
experience complete pain relief.
Rodriguez-Navarro et al Regional Anesthesia and Pain Medicine 2011;
36:103-109
42. When comparing Bupivacaine and NeoSTX
patients, NeoSTX patients, recovered almost 2
days sooner (3.8 days vs. 5.7 days).
Global Postoperative Recovery Score
43. Rat Sciatic Blockade: Additional Prolongation by
Epinephrine Added to NeoSTX-Bupivacaine (2012)
Green Arrows:
Epinephrine effect:
6-fold prolongation
of full block, 3 – fold
prolongation of half-
block compared to
Neo-Bup; > 10-fold
compared to Bup
43
47. Phase 1 Study: Aims
1. Evaluate Local and Systemic Safety of
NeoSTX combined with Bup +/- epi
2. Characterize NeoSTX PK
3. Dose-Response for Cutaneous Sensory
Block Intensity and Duration
i. NeoSTX plain (in saline)
ii. NeoSTX-Bupivacaine
iii. Bupivacaine plain (comparator)
iv. Add-On Amendment Study:
NeoSTX-Bupivacaine-Epinephrine
47
48. Subcutaneous Infiltration
• Two injections simultaneously in a 3x3cm square
area of skin of the posterior calf; one on each side
NeoSTx + saline
NeoSTx + BupivacaineBupivacaine
(0.2%)
Saline (placebo)
Control Test
48
49. Primary Outcome: Safety Parameters
• Symptom scores
– Tingling or numbness of lips, tongue or fingers
– Nausea or vomiting, Dizziness
• Subclinical Physiologic Measures
– Maximum negative inspiratory force (NIF)
– Vital capacity (FVC)
– Grip strength
• Clinical Physiologic Measures
– Oxygen saturation or EtCO2
– Hemodynamics and ECG
49
50. Secondary outcome measures:
PK-PD profiling
• Pharmacokinetics: uptake and distribution
of NeoSTX
–Blood and urine samples
• Pharmacodynamics:
–Cutaneous sensory blockade (numbness)
by QST
50
51. Phase 1: Safety
• No medical intervention or supplemental 02.
• Reassuring 02 sat, BP, NIF, VC, grip strength, ECG
• Transient mild tingling of lips, tongue and fingertips
began at 15 mcg
• Increasing tingling with escalation to 40 mcg
• Transient nausea and emesis at 40 mcg.
• Symptoms generally resolved within 1 hour.
• Addition of epinephrine dramatically suppressed
systemic symptoms.
• No local or systemic sequelae.
Lobo et al Anesthesiology 2015
51
55. Time to near-complete recovery of cutaneous mechanical
thresholds in 10 and 30mcg NeoSTX-Saline, NeoSTX-Bup, and
NeoSTX-Bup-Epi treatment groups.
56. Potential Impact of NeoSTX for
Prolonged-Duration Local Anesthesia
• Greater safety with large doses/volumes
• Utility both intra-op and post-op
• OR work-flow - single-shot blocks more than
catheters
• Wider spread of initial injectates versus
infusions
• Reliability – if you prove a block is working pre-
op, you should have 2 – 3 days of analgesia
• Impact in resource-limited countries
57. Example: a 3-Day Ultrasound-Guided Paravertebral
Single-Shot Block Instead of a Catheter
(Paravertebral or Thoracic Epidural) for Thoracic
and Abdominal Surgery
58. Conclusions
• Prolonged duration local anesthesics
should transform postoperative pain
relief and accelerate recovery
• Neosaxitoxin is a promising candidate
for achieving these goals.
• Drug development takes time and
persistence.
• Our progress to date was made
possible by the unique resources and
collaborations available at Boston
Children’s Hospital