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Pain Medicine 2015; 16: 13–17
Wiley Periodicals, Inc.
EDITORIAL
Long-Acting Local Anesthetic Agents and
Additives: Snake Oil, Voodoo, or the Real Deal?
Supported by the University of Florida. The authors
disclose no conflicts of interest.
The onset, spread, density, and duration of a nerve block
are functions of what local anesthetic drug is injected,
where it is injected, and for how long the nerve is exposed
to it. Over the past 27 or more years, as far back as 1988
[1], researchers and companies, initially with topical tetracaine [1], and later as injectable liposomal bupivacaine
[2], have been searching for the “magic bullet” to be
injected somewhere near a nerve, or infiltrated into tissue,
that will eliminate a patient’s acute or perioperative pain
for as long as the pain lasts without unwanted side
effects. The work of the Williams and colleagues,
reported in this edition of Pain Medicine, is a further report
on such efforts [3–5]. Although we have no or very little
evidence of this, which points to a bigger problem eluded
upon below, we instinctively know that most pain, especially surgical pain, outlasts our single-injection blocks,
and we also know that we have to offer patients nerve
blocks that last at least as long as the pain does without
causing discomfort and unwanted side effects.
Over the years, the challenge of developing a blocking drug
that lasts long enough to outlast pain but that does not
have similarly long-lasting unwanted side effects has been
addressed by combining different drugs and developing
new presentations of drugs. Few adjuvant agents, other
than perhaps dexamethasone, have stood the test of time
[6]. Another attempt was to add epinephrine to the existing
arsenal of drugs [7] to cause vasoconstriction and
decreased blood flow, thus slowing down the washout of
the drugs and increasing the time that the nerve is exposed
to the local anesthetic agent. We now know, that epinephrine does not increase the duration of action of bupivacaine
or ropivacaine [7]; if anything, epinephrine can shorten the
onset of a nerve block with bupivacaine, increase the density of such blocks, and increase the duration of some
drugs like lidocaine, for example, by causing nerve ischemia [8] if used for nerve blocks. Workers like Dag Selander
et al. [8], among many others, have conclusively shown
years ago that this ischemia can cause nerve injury.
Adding dexamethasone has been met with enthusiasm
[6,9] because it seemed to extend the analgesic duration
of a single-injection nerve block from an average of
730 minutes (12 hours) to around 1,306 minutes
(21 hours), as reported in a recent meta-analysis of studies
that involved 801 patients [9]. The authors also reported
an increase in the duration of a motor block from 664
minutes (11 hours) to 1,102 minutes (18 hours). Desmut
and colleagues [10], however, reported in a study of 150
patients that intravenous (IV) dexamethasone is equivalent
to perineural dexamethasone in prolonging the analgesic
duration of single-injection interscalene block with ropivacaine for arthroscopic shoulder surgery. Both IV and perineural dexamethasone almost doubled the duration from
757 (635–910) minutes of the sensory block. However, we
already know that systemic (IV) dexamethasone has analgesic effects [11]. Systemic response to injury and its role
in pain, the pain cascade, and pain mediators are important to mention [12]. Nerve blocks usually preempt (surgical) injury, whereas local infiltration of local anesthetic
agents is usually administered after surgical trauma. It may
well be that nerve blocks, combined with systemic steroids, are a more complete approach than a single injectable agent. In a recent large meta-analysis, De Oliveira and
coworkers [11] showed that IV dexamethasone significantly reduces postoperative pain and opioid consumption.
The
question,
therefore,
was
whether
dexamethasone, if injected perineurally, could add any
value without adding neurotoxicity. The study the Williams
et al. reported in this edition of Pain Medicine [3] demonstrated that dexamethasone and other agents such as clonidine and buprenorphine, when combined with
bupivacaine, caused no long-term motor or sensory deficits or damage to the sciatic nerves or dorsal root ganglia
of rats. These findings, for dexamethasone at least, support the findings of a recent meta-analysis that reported no
persistent nerve palsy in 180 patients who received perineural dexamethasone [8].
A further attempt at finding the “magic bullet” has been to
engineer slow-release local anesthetic agents, for example, in liposomal spheres [2,13] (Exparel, Pacira Pharmaceuticals, Parsippany, NJ, USA), or in an organic matrix
of sucrose acetate isobutyrate [14] (Posidur [SABERBupivacaine], Durect Corporation, Cupertino, CA, USA).
Medication encapsulated within liposomes, including
drugs such as ibuprofen, opioids, vitamins, cancer chemotherapeutic agents, and local anesthetic agents, is
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Boezaart et al.
slowly released because of the gradual breakdown of the
lipid vesicles. Unlike their cousins, however, for whom
slow release has been proven to be advantageous (liposomal vitamin C, liposomal glutathione, etc.), emerging literature [14] is unconvincing in proving the virtues of
liposomal bupivacaine and suggests that it does not fulfill
the promises it originally held for hemorrhoid [15,16] and
bunion surgery [17]. In contrast to these findings, manufacturers heavily market it to surgeons. If it could extend
the effects of a single-injection nerve block, for which it
has not yet been approved by the Food and Drug Administration, for up to 72–96 hours, it would most probably
be hugely unpopular and would probably self-destruct
because few patients are likely to tolerate a 72- to 96hour motor, proprioception, and sensory nerve block.
Similarly, very few patients would, for example, tolerate a
3- to 4-day phrenic nerve block or a 3- to 4-day quadriceps muscle block. Its use for tissue infiltration for surgery
resulting in high pain levels such as knee and hip replacement surgery is also proving to be disappointing [18].
Market penetration and utilization has far outpaced science and data to support its use. In a recent study, the
periarticular infiltration of 20 mL of 1.3% (266 mg) liposomal bupivacaine [18] after total knee arthroplasty provided inferior pain control compared with the 100 times
cheaper 30 mL of 0.5% bupivacaine (150 mg) in
1:200,000 epinephrine. Another article by Barington and
colleagues [19], which was supported by an educational
grant from the manufacturers of liposomal bupivacaine,
presents weak data for its successful use. In 2007, Parvataneni and coworkers [20] reported successful use of a
multimodal periarticular injection consisting of bupivacaine (200–400 mg), morphine sulfate (4–10 mg), epinephrine (300 mcg), methylprednisolone acetate (40 mg),
and cefuroxime (750 mg) in normal saline. However,
when bupivacaine alone was injected into the hip joint
capsule after total hip arthroplasty, it, similar to liposomal
bupivacaine [19], faired no better, or only marginally better than placebo [21]. The data strongly suggest that it is
most likely the other drugs (morphine, and steroidal and
other multimodal agents) that have the analgesic effect
and not the local anesthetic agent.
Encapsulated morphine for epidural use was originally
met with great enthusiasm [22], but because of the
plethora of unwanted and even dangerous side effects
that ranged from itching (51%), nausea (76%), vomiting
(53%), and a large percentage (16%) of respiratory
depression for a relatively long time in one study [20], it
basically disappeared from general use.
To put it bluntly, if a drug can cause a long-acting nerve
block effect, it most likely can also cause long-acting
unwanted side effects. Furthermore, even doubling the
effective time of any short-acting local anesthetic agent by
any means, no matter how safe, when the agent wears off,
it will still unmask the untreated severe pain of surgical
insults that usually last for days and even weeks, not just
for hours. The work of the Williams et al. [3–5], as reported
in this issue of Pain Medicine, is a further effort to minimize
these unwanted side effects and maximize the positive
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ones. This is a very noble effort that should be wholeheartedly supported and congratulated because if they succeed, the implications could be huge. For example,
imagine the impact of empowering a medic on the battlefield who can do a quick, easy, and safe nerve block on a
fellow soldier who is wounded, and the block can last 30–
72 hours, keeping the soldier free of pain until he/she can
be transferred to a field hospital or other advanced medical
facility. As with so many other advances in medicine that
originated in the military, a long-acting local anesthetic
agent may very well be another one of these developments. Even continuous nerve blocks were first performed
in 1975 in an austere war situation [23].
To understand the onset and duration of nerve blocks,
however, we need to understand the microanatomy of
peripheral nerves.
Figure 1 is a summary of the important recent work of
Anderson and colleagues [24] in elegant dissections of
peripheral nerves and Karmakar and colleagues [25] with
their excellent work with high-definition ultrasound to help
us understand the “sweet spot” [24] of a nerve. Unlike an
electrical current that can readily cross over anatomical
barriers [26], even over the skin [27], local anesthetic
agents cannot easily cross over biological membranes
[28]. If they could easily cross over anatomical and physiological barriers, they would be highly toxic and unusable
[29]. Local anesthetic drugs complete their action on the
sodium channels of nerve axons by diffusing to the axons
(Figure 1, areas 13–16). This diffusion takes place against
a concentration gradient following Fick’s Law [28] (simplified as dQ/dt 5 P 3 DC, where dQ/dt is the rate of passive diffusion, P is the permeability constant of the drug,
and DC is the concentration gradient). A local anesthetic
drug injected on the far side of a barrier or biological
membrane, or a number of membranes, will take much
longer to reach the axons (if at all) than the same drug
injected on the same (near) side of the membrane or
sheath as the axons, and the duration of action, will be
significantly shorter. To illustrate, a drug injected into a
nerve fascicle deep to the perineurium (Figure 1, area 11)
would have a very fast, almost immediate, onset of
action, and the action would last for weeks, if not
months—the typical numb thumb 5 weeks after an intrafascicular injection during an axillary nerve block. The
same drug, on the other hand, injected into a muscle
near a nerve or in the subepimyseal space (Figure 1, area
6) would have a very slow onset (if at all), and the local
blood flow would remove the drug so that the action
would be very short. A drug injected into the subparaneural space (recently more correctly named the subcircumneural space [30]) (Figure 1, area 8), the “sweet spot” of
the nerve [30], will have a short onset of action, and
depending on the volume and concentration and type of
drug, the density and duration of the single-injection
block would vary. If, however, a drug that has a 3- to 4day action on the axons was injected into the subcircumneural space (Figure 1, area 8) and the drug is not readily
removed by the local blood flow, all the axons would be
blocked, causing a block not only of pain fibers but also
Editorial
Figure 1 Microanatomy of the ulnar nerve (1). Basilic vein (2), brachial vein (3), and brachial artery (4) among
others share a common epimysium (5). Deep to this fascia layer is the subepimyseal space (6) that forms the well
known “doughnut sign” on ultrasound if fluid is injected into it. The ulnar nerve is surrounded by the circumneural
sheath (7) (also referred to as the “paraneural sheath”), which is a thin but tough layer (previously, especially in
neurosurgical texts, referred to as the “gliding apparatus”), and deep to this sheath is the subcircumneural space
(8)—the “sweet-spot” of the nerve. Each nerve is in turn surrounded by an epineurium (9), which houses the
nerve fascicles (10). Each nerve fascicle is surrounded by a tough and relatively noncompliant perineurium (11),
which is thought to be embryological remnants of the dural sheath that surround nerve roots at the paravertebral
level. The fluid and fibrous collagen inside the fascicles forms the endoneurium (12), and the a-, c-, c-, and bfibers (13–16) are situated in the endoneurium (Reprinted with the kind permission of Mary K. Bryson).
of sensory, motor, and proprioception fibers—something
probably very few patients would tolerate. If that same
drug were injected on the far side of a barrier or a number
of barriers, the concentration of the drug, for example,
released by liposomes, would probably be too low and
would be removed too quickly to have any effect.
What we desperately need today is a drug or treatment
modality that can selectively block sensory nerves and
pain fibers that can be turned on and off as the need
exists and that can outlast surgical pain. We need blocks
that we can increase the spread of (to block more nerves
if we need to; for example, more epidural roots or roots or
cords of the brachial plexus), that we can control the density of by changing the concentration of the drug used,
and that we can increase the motor component if we
need to, for example, in rotator cuff surgery, or decrease
the motor component to facilitate earlier mobilization and
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Boezaart et al.
ambulation. We need to be able to control the density of
the block to facilitate feeling but have it dense enough to
block only the pain fibers of a nerve, and we need to be
able to turn the block off when the pain has subsided and
the block is no longer needed. We also need to be able to
reinitiate the block if the pain returns or the block has
been turned off prematurely.
We believe our research efforts and energy and resources
should be spent on the above by promoting the establishment of more subspecialty acute pain services, further
developing, for example, continuous peripheral nerve
blocks [31] and delivery devices (pumps and catheter
systems), etc., that we as practitioners can control. Surgeons and especially patients are fearful of pain and are
therefore willing to try almost anything given enough suffering, but this dilutes the science of perioperative pain
management, and this should further bolster support for
acute pain medicine as a subspecialty. The development
of long-acting, single-injections blocks, except for exceptional use in mild to moderate intermediate pain situations
that are perhaps better served by other systemic and
enteral analgesic regimes, and military use of course, will
most probably not advance our cause of properly caring
for patients with acute pain and for patients with longerlasting, hideous pain such as pain caused by cancer [32].
Obviously, despite decades of research, the manufacture of products (many of which have fizzled), and the
creation of techniques (including minimally invasive surgery), the treatment of pain remains a major issue,
which means no clear winner has emerged. If the goal
is to get the patient out of the recovery room, then
most additives are useful. But if the goal is to treat
patients with pain rather than pain itself, there is a good
reason why many ideas and drugs have fizzled out over
time. Ultimately, the truth will prevail and the patient
with pain will be the final arbiter of this truth.
The gallant, brave, and forward-looking efforts of Trip
Buckenmaier, Patrick Tighe, and many others [33] to
establish acute pain medicine as a subspecialty should
receive the full and continuous support of all medical
practitioners. A structured discipline of acute pain medicine would help to establish vibrant acute pain services
and would contribute to the understanding of the pathophysiologic response to injury and its role in acute pain
through systemic pathways that may trigger more inflammation, pain, swelling, and immobility for weeks (months
in some patients), complex regional pain syndrome in
some, and progression to chronic pain syndromes that
develop after injury (including surgery) in others. Only then
will we finally be able to offer patients nerve blocks and
other treatment modalities that outlast their pain.
ANDRÉ P. BOEZAART, MD, PhD,*† YURY ZASIMOVICH, MD,*
and HARI K. PARVATANENI, MD†
Departments of *Anesthesiology and
†
Orthopaedics, College of Medicine, University of
Florida, Gainesville, Florida, USA
16
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