OPIATE TOLERANCE AND ADDICTION
The mechanisms of dependence and tolerance involve genetic, molecular,
cellular, physiologic, and functional factors. In the locus caeruleus, the major
noradrenergic nucleus in the brain, long-term opioid exposure results in inhibition
of adenyl cyclase, reduced activity of protein kinase A, and upregulation of the
cAMP pathway.[229]
Changes in μ-receptor density
that occur prior to or during the development of tolerance do not appear to be essential
for development of opioid tolerance.[230]
Possible
mechanisms involve protein kinase signal transduction cascades that link extracellular
signals to cellular changes by regulating target gene expression. Much work remains
to be done in order to fully elucidate the complex mechanisms of tolerance.[231]
[232]
Acute administration of opioids results in analgesia and side
effects, whereas tolerance and dependence were thought to occur only after chronic
administration. However, it has become more recently recognized that tolerance can
also develop rapidly after an acute opioid exposure in animals and humans.[233]
[234]
[235]
Intraoperative
remifentanil infusion (0.3 µg/kg/minute) in patients undergoing major abdominal
surgery under desflurane anesthesia increased postoperative pain and morphine requirement
compared with low-dose remifentanil (0.1 µg/kg/minute), suggesting the development
of acute remifentanil tolerance.[236]
In contrast,
there is a report that target-controlled infusion of alfentanil and remifentanil
for postoperative analgesia does not lead to opioid tolerance.[237]
In human volunteers, continuous infusion of remifentanil (0.08 µg/kg/minute)
for 3 hours did not decrease the pain threshold.[238]
Thus, the development of acute opioid tolerance in humans remains controversial.
Opioids can elicit hyperalgesia in experimental models after repeated opioid administration
or continuous delivery.[239]
This phenomenon seems
to be related to opioid tolerance.[240]
In rats,
thermal hyperalgesia and mechanical allodynia were observed for several days after
cessation of morphine administration (40 mg/kg/day for 6 days).[241]
The opioid-induced hyperalgesia was shown to be due to spinal sensitization to glutamate
and substance P.[242]
Furthermore, cholecystokinin
and the NMDA-nitric oxide (NO) system are responsible for the development of acute
tolerance to opioids,[243]
which is also affected
by spinal serotonin activity.[244]
There have been
reports that opioid-induced hyperalgesia and subsequent acute opioid tolerance can
be prevented by ketamine, suggesting the involvement of the NMDA receptor.[245]
[246]
Peripheral morphine effects have been suggested to be less prone
to tolerance.[247]
Thus, the method and schedule
of drug administration may also affect the development of tolerance.[248]
However, modifying an opioid administration schedule to modulate the development
of tolerance may not always be useful or effective.[249]
Certain patients may appear to be tolerant to opioids, but instead they may suffer
from pathophysiologic conditions, such as neuropathies, that are poorly responsive
to opioids.[250]
Management of the Opioid-Dependent Patient
Problems in the opioid-addicted patients include cardiopulmonary
problems, restrictive lung disease, increased alveolar-arterial O2
gradients,
renal disease and anemia. Long-term morphine administration causes adrenal hypertrophy
and impairs corticosteroid secretion. Viral and nonviral hepatitis, acquired immunodeficiency
syndrome, osteomyelitis, muscle weakness, and neurologic complications may be found
in addicted patients.
Anesthetic management for the opiate-dependent or addicted patient
should include adequate premedication with opioids. There is no ideal anesthetic
agent or technique to employ in the chronic addict or in the patient with an acute
opiate overdose. Cardiovascular and respiratory changes in the patient with acute
opioid overdose can be reversed with increments of naloxone (40–80 µg
every 1 to 2 minutes IV) until vital signs are adequate. Support of the circulatory
system with fluids and monitoring of arterial blood gases and pulmonary function
are also important.
Recently, as treatment for opioid addiction, rapid detoxification
with high doses of naloxone or naltrexone has been reported. For this treatment,
general anesthesia is induced before the start of opioid antagonism and maintained
for several hours to prevent the perception of withdrawal symptoms by the patient.
[251]
[252]
Blockade
of μ-opioid receptors by naloxone (total dose of 12.4 mg) in opioid-addicted patients
induces sympathetic neural activation, including increase in plasma catecholamine
concentration and cardiovascular stimulation, which is abolished by α2
-agonists.
[253]
