The lecture discusses the advantages and limitations of existing local anesthetics and the potential impact of new long-acting anesthetics like neosaxitoxin on clinical practice. Current local anesthetics often have short durations and systemic toxicity risks, while new developments, such as the use of liposomal formulations and site-1 sodium channel blockers, aim to enhance efficacy and safety. Neosaxitoxin shows promise in improving postoperative pain relief and recovery times, warranting continued research and development efforts.

1. Long-Acting Local Anesthetics:
Present and Future
Joseph Cravero MD FAAP
Charles Berde MD, PhD
34th SSAI Congress
Sept 8 2017,

2. NO DISCLOSURES FOR ME

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

4. Despite Major Advances,
Surgery is Still Painful

5. Opioids are Partially Effective, but
with Side-Effects and Risks
• Somnolence, Mental Clouding
• Respiratory Depression
• Nausea and GI Dysfunction
• Addiction

6. How do we use local anesthetics?

7. Wound Infiltration During Surgery

8. Ultrasound Guided
Regional Anesthesia

9. Clinical Outcomes of Regional Anesthesia
• Improved Pain Scores
• Opioid Sparing
• Accelerated Recovery (Hospital Stay, GI
Function)
• Long-Term Outcomes (Rehabilitation, Chronic
Pain, Cancer Progression)

10. Extracellular
Intracellular
= Na+
Voltage-gated
Sodium Channel
+
-

11. Resting
Activated
(Open)
Inactivated

12. Resting
Activated
(Open)
Inactivated
= Local Anesthetic
Modulated Receptor Hypothesis

13. Currently Available
Local Anesthetics
are not Ideal.

14. Local Anesthetics are
“Dirty Drugs”.
• Low potency (10 – 300 mg)
• Toxicity near therapeutic dose
• Multiple cellular actions.

15. Other Sites of Action of
Local Anesthetics
• Calcium channels
• Potassium channels
• TRPV1 receptor-channels
• Mitochondrial electron-transport
• Macromolecular assembly

16. Major Structural Constraint:
• Must dissolve well and diffuse
rapidly in both aqueous and
lipophilic micro-environments.

17. Most Drugs
Injection or
absorption
site
Central
circulation
Effect
site
Metabolism
and
elimination

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

21. Long Acting Local Anesthetics

22. Controlled-Release of Bupivacaine
and Other Local Anesthetics
• Liposomes
• Depo-Foam
• Polymer Microparticles

23. Microspheres containing Bupivacaine 70% with
Dexamethasone 0.05% and PLGA Polymer 29.5%

24. Phospholipid-Based Delivery Systems

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

32. Rat Sciatic Nerve Block for
Local Anesthetic Testing

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

35. Epinephrine prolongs nerve blockade by
> 10-fold.

37. 0
0.2
0.4
0.6
0 15 30 45 60
0
0.2
0.4
0.6
0 15 30 45 60
0
0.5
1
1.5
2
0 15 30 45 60
TTX60μM TTX60μM with Epinephrine
Sciatic
Nerve
Peri-
sciatic
Muscle
0.5
1.5
0
1
2
0 15 30 45 60
BloodFlow(ml·min-1·g-1)
BloodFlow(ml·min-1·g-1)
BloodFlow(ml·min-1·g-1)
BloodFlow(ml·min-1·g-1)
Time (min) Time (min)
Time (min) Time (min)
*
*
†
A
DB
C
Regional Blood Flow in Muscle and Nerve
Masuda, Cairns, Sadhasivam, Berde Anesthesiology 2004

38. Neosaxitoxin

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

44. Excellent Hemodynamic Stability with
Intravenous NeoSTX (Sheep)

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

52. 0
10
20
30
40
50
60
70
80
90
100
Percentage(%)
NeoSTX dose
Tingling
Numbness
Figure 2: Clinically significant ( > 2 /10, lasting > 30
minutes) numbness and tingling after NeoSTX
52

53. 0
50
100
150
200
250
0 200 400 600 800 1000 1200 1400
NeoSTX(pg/mL)
Time (min)
NeoSTX (N = 5) NB (N = 5) NBE (N = 8) Saline (N = 2)
NeoSTX Plasma Concentrations Versus Time
NeoSTX concentration = 30mcg+/-additives as labelled; Mean PK presented for each group

54. Prolonged Skin Numbness and Pain
Insensitivity with NeoSTX Combinations

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