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

Routes of Administration Available. The aim in chronic pain states
is to prefer to employ the least invasive routes of drug administration,
which include oral, buccal, or transdermal delivery. IV routes are
more useful in perioperative in-hospital pain management and during
end-of-life care. Patients with chronic pain states where side
effects from systemic drug exposure are intolerable and are candidates
for spinal drug delivery; however, this may require surgery for
indwellng catheterization and pump placement.
Dose Selection/Titration. The conservative approach to the initiation
of chronic opioid therapy suggests starting with low doses that
may be incremented on the basis of the pharmacokinetics of the
drug. In chronic pain states, the aim would be the use of long-acting
medications to permit once or twice daily dosing (e.g., controlled
release formulations or methadone). Such agents reach steady-state
slowly. Rapid incrementation is to be avoided and rescue medication
should be made available for breakthrough pain during initial
dosing titration.
Opiate Rotation. Opioid rotation is the practice of changing to a
different opioid when the patient either fails to achieve benefit or
side effects are reached before analgesia is sufficient. In a retrospective
review, it was found that the first opioid prescribed was effective
for 36% of patients, was stopped because of side effects in 30%, and
was stopped for ineffectiveness in 34% (Quang-Cantagrel et al.,
2000). Of the remaining patients, the second opioid prescribed after
the failure of the first was effective in 31%, the third in 40%, the
fourth in 56%, and the fifth in 14%. Thus, if it is necessary to change
the opioid prescription because of intolerable side effects or ineffectiveness,
the cumulative percentage of efficacy increases with each
new opioid tested. Failure or intolerance of one opioid cannot necessarily
predict the patient’s response or acceptance to another.
Practically, opioid rotation involves incrementing the dose of a given
opioid, e.g. morphine, to one limited by side-effect and insufficient
analgesia. At this point an alternate opioid medication at an equieffective
dose may be substituted for the first medication. Agents typically
involved in such rotation sequences are various oral opioids
such as morphine, methadone, dilaudid, and oxycodone and the fentanyl
patch systems. Care must be taken to titrate the doses and monitor
the patient closely during such drug transitions.
Combination Therapy. In general, the use of combinations of drugs
with the same pharmacological kinetic profile is not warranted (e.g.,
morphine plus methadone). Nor if the drugs have overlapping targets
and opposing effects (e.g., combining a MOR agonist with an agent
having mixed agonist/antagonist properties). On the other hand, certain
opiate combinations are useful. For example, in a chronic pain
state with periodic incident or breakthrough pain, the patient might
receive a slow-release formulation of morphine for baseline pain
relief and the acute incident pain may be managed with a rapidonset/short-lasting
formulation such as buccal fentanyl.
For inflammatory or nociceptive pain, it is routinely recommended
that opioids be combined with other analgesic agents, such
as NSAIDs or acetaminophen. In this way, one can take advantage
of the analgesic effects produced by the adjuvant and minimize the
dose requirement of the opioid. In some situations, NSAIDs can provide
analgesia equal to that produced by 60 mg codeine. The analgesic
synergism between opioids and aspirin-like drugs is discussed
below and in Chapter 34. In the case of neuropathic pain, other drug
classes may be useful in combination with the opiate. For example,
antidepressants that block amine reuptake, such as amitriptyline or
duloxetine, and anticonvulsants such as gabapentin, may enhance
the analgesic effect and may be synergistic in some pain states.
Different classes of drug may have distinguishable efficacy in different
models of pain processing (Table 18–8).
The “opioid-sparing” strategy is the backbone of the “analgesic
ladder” for pain management proposed by the World Health
Organization. Weaker opioids can be supplanted by stronger opioids
in cases of moderate and severe pain. Antidepressants such as duloxetine
and amitriptyline are used in the treatment of chronic neuropathic
pain but have limited intrinsic analgesic actions in acute pain.
However, antidepressants may enhance morphine-induced analgesia
(Levine et al., 1986).
NON-ANALGESIC THERAPEUTIC
USES OF OPIOIDS
Dyspnea
Morphine is used to alleviate the dyspnea of acute left ventricular
failure and pulmonary edema, and the response to intravenous morphine
may be dramatic. The mechanism underlying this relief is not
clear. It may involve an alteration of the patient’s reaction to
impaired respiratory function and an indirect reduction of the work
of the heart owing to reduced fear and apprehension. However, it is
more probable that the major benefit is due to cardiovascular effects,
such as decreased peripheral resistance and an increased capacity of
the peripheral and splanchnic vascular compartments. Nitroglycerin,
which also causes vasodilation, may be superior to morphine in this
condition (Hoffman and Reynolds, 1987). In patients with normal
blood gases but severe breathlessness owing to chronic obstruction
of airflow (“pink puffers”), dihydrocodeine, 15 mg orally before
exercise, reduces the feeling of breathlessness and increases exercise
tolerance (Johnson et al., 1983). Nonetheless, opioids generally
are contraindicated in pulmonary edema unless severe pain also is
present.
Anesthetic Adjuvants
High doses of opioids, notably fentanyl and sufentanil, are widely
used as the primary anesthetic agents in many surgical procedures.
They have powerful “MAC-sparing” effects’, e.g., they reduce the
concentrations of volatile anesthetic otherwise required to produce
an adequate anesthetic depth. Although respiration is so depressed
that physical assistance is required, patients can retain consciousness.
Therefore, when using opioids as the primary anesthetic agent,
it is important to use in conjunction with an agent that results in
unconsciousness and produces amnesia such as the benzodiazepines
or low concentrations of volatile anesthetics. High doses of opiate
also result in prominent rigidity of the chest wall and masseters
requiring concurrent treatment with muscle relaxants to permit intubations
and ventilation.
TREATMENT OF ACUTE
OPIOID TOXICITY
Acute opioid toxicity may result from clinical overdosage,
accidental overdosage, or attempts at suicide.
Occasionally, a delayed type of toxicity may occur from