Prolonged Infusions of Local Anesthetics, Tachyphylaxis,
and Development of Long-Duration Local Anesthetics (see also
Chapter 72
and Chapter
73
)
Local anesthetics are increasingly being administered by continuous
infusion for several days after surgery or for periods of weeks to months for the
treatment of chronic malignant and nonmalignant pain. With prolonged infusions,
there is potential for delayed systemic accumulation and toxicity. Continuous infusions
of bupivacaine of up to 30 mg/hr in adults for up to 2 weeks produced no overt CNS
or cardiac toxicity despite total plasma bupivacaine concentrations in the range
of 2 to 5 µg/mL in several patients.[212]
Apparent reductions in the effectiveness of local anesthetic infusions
may be due to a number of causes unrelated to tolerance per se, including dislodgement
of epidural catheters and changes in the dermatomal origin or intensity of nociceptive
input. In obstetric patients receiving epidural bolus injections, recurrence of
pain before the next injection resulted in a reduction in the intensity and duration
of blockade, whereas repeat injection before the return of pain prevented this rapidly
occurring form of tolerance, or tachyphylaxis.[73]
In post-operative patients, the coadministration of systemic opioids prevented regression
of segmental blockade in patients receiving thoracic epidural bupivacaine infusions.
[213]
Studies in rats suggest that both pharmacokinetic
and pharmacodynamic mechanisms are involved. In a rat model, tachyphylaxis was linked
to the development of hyperalgesia,[214]
and drugs
that inhibited hyperalgesia, including N-methyl-D-aspartate
receptor antagonists[215]
and nitric oxide synthase
inhibitors,[216]
also prevented tachyphylaxis.
Conversely, repeated sciatic injections of lidocaine produced reduced intraneural
lidocaine content along with a reduced duration of block.[99]
Several methods are under investigation to produce long-duration
nerve blockade. Liposomal encapsulation can prolong blockade, depending on the dose
and the physical properties of the liposome (surface charge, size, lamellar structure).
[217]
[218]
Local
anesthetics can be incorporated into biodegradable polymer microspheres for sustained
release. These preparations produce peripheral nerve block in animal models[219]
ranging from 2 to 8 days, depending on the dose, site, and species.[220]
Prolonged-duration local anesthesia also appears to be feasible
with the use of site 1 sodium channel toxins in combination with either local anesthetics
or adrenergics.[221]
Other drugs have been examined
for use as local anesthetics, including tricyclic antidepressants.[222]
It remains to be determined whether local anesthetics with prolonged
duration will receive widespread use in clinical practice. If they prove safe and
effective, they may have potential use in intercostal blockade and wound infiltration,
particularly for surgery on the thorax and abdomen, where protective sensation is
comparatively less important than for limb surgery. If drugs can be developed that
last for weeks or longer, they may have additional applications in the management
of chronic pain and cancer pain.
