DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Table 18–3
Epidural or Intrathecal Opioids for the Treatment of Acute (Bolus) or Chronic (Infusion) Pain
SINGLE INFUSION DURATION OF EFFECT OF
DRUG DOSE (mg) a RATE (mg/h) b ONSET (min) A SINGLE DOSE (h) c
Epidural
Morphine 1-6 0.1-1.0 30 6-24
Meperidine 20-150 5-20 5 4-8
Methadone 1-10 0.3-0.5 10 6-10
Hydromorphone 1-2 0.1-0.2 15 10-16
Fentanyl 0.025-0.1 0.025-0.10 5 2-4
Sufentanil 0.01-0.06 0.01-0.05 5 2-4
Alfentanil 0.5-1 0.2 15 1-3
Subarachnoid (Intrathecal)
Morphine 0.1-0.3 15 8-24+
Fentanyl 0.005-0.025 5 3-6
a
Low doses may be effective when administered to the elderly or when injected in the thoracic region.
b
If combining with a local anesthetic, consider using 0.0625% bupivacaine. c Duration of analgesia varies widely; higher doses produce longer duration.
With the exception of epidural/intrathecal morphine or epidural sufentanil, all other spinal opioid use is considered to be off label.
Adapted from International Association for the Study of Pain, 1992.
have a longer residence times in the cerebrospinal fluid; as a consequence,
after intrathecal or epidural morphine, delayed respiratory
depression can be observed for as long as 24 hours after a bolus dose.
While the risk of delayed respiratory depression is reduced with more
lipophilic opioids, it is not eliminated. Extreme vigilance and appropriate
monitoring are required for all opioid-naïve patients receiving
intraspinal narcotics. Use of intraspinal opioids in the opioid-naïve
patient is reserved for postoperative pain control in an inpatient monitored
setting. Epidural administration of opioids has become popular
in the management of postoperative pain and for providing
analgesia during labor and delivery. Lower systemic opioid levels are
achieved with epidural opioids, leading to less placental transfer and
less potential for respiratory depression of the newborn (Shnider and
Levinson, 1987). Many opioids and other adjuvants are commonly
used for neuraxial administration in adults and children; however, the
majority of agents employed have not undergone appropriate preclinical
safety evaluation and approval for these clinical indications; thus,
such uses are “off-label”. Thus, at this time, those agents approved for
spinal delivery are certain preservative-free formulations of morphine
sulfate (DURAMORPH, DEPODUR, others) and sufentanil (SUFENTA). It is
important to remember that the spinal route of delivery represents a
novel environment wherein the neuraxis may be exposed to exceedingly
high concentrations of an agent for an extended period of time
and safety by another route (e.g., PO, IV) may not translate to safety
after spinal delivery (Yaksh and Allen, 2004).
Patients on chronic spinal opioid therapy are less likely to
experience respiratory depression. Selected patients who fail conservative
therapies for chronic pain may receive intraspinal opioids
chronically through an implanted programmable pump.
Analogous to the relationship between systemic opioids and
NSAIDs, intraspinal narcotics often are combined with other agents
that include local anesthetics, N-type Ca 2+ channel blockers (e.g.,
ziconotide), α 2
adrenergic agonists, and GABA B
agonists. This permits
synergy between drugs with different mechanisms allowing the use
of lower concentrations of both agents, minimizing side-effects and
the opioid-induced complications (Wallace and Yaksh, 2000).
Local Drug Action
Opioid receptors on peripheral sensory nerves respond to locally
applied opioids during inflammation (Stein, 1993). Peripheral analgesia
permits the use of lower doses, applied locally, than those necessary
to achieve a systemic effect. The pain relief generated by this
route of delivery is limited but the technique has been demonstrated
to have some efficacy in postoperative pain (Stein, 1993).
Development of such compounds and expansion of clinical applications
of this technique are active areas of research.
Rectal Administration
This route is an alternative for patients with difficulty swallowing or
other oral pathology and who prefer a less invasive route than parenteral
administration. This route is not well tolerated by most children.
Onset of action is within 10 minutes. In the U.S., only morphine
and hydromorphone are available in rectal suppository formulations.
Inhalation
Opioids can be delivered by nebulizer. However, this delivery
method is rarely used due to erratic absorption from the lung and
highly variable therapeutic effect.
Oral Transmucosal Administration
Opioids can be absorbed through the oral mucosa more rapidly than
through the stomach. Bioavailability is greater owing to avoidance of
first-pass metabolism, and lipophilic opioids are absorbed better by
this route than are hydrophilic compounds such as morphine. A
transmucosal delivery system that suspends fentanyl in a dissolvable
sugar-based lollipop (ACTIQ, others) or rapidly dissolving
buccal tablet (FENTORA) have been approved for the treatment of cancer
pain; in this setting, transmucosal fentanyl relieves pain within
15 minutes, and patients easily can titrate the appropriate dose.