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

516 significantly (Du Pen et al., 1999). The next sections
provide guidelines for rational drug selection, discuss
routes of administration other than the standard oral and
parenteral methods, and outline general principles for
the use of opioids in acute and chronic pain states.
SECTION II
NEUROPHARMACOLOGY
Guidelines for Opiate Dosing
Whereas the World Health Organization three-step ladder
was initially targeted at the treatment of cancer pain,
it is accepted practice to use this three-step ladder to
treat chronic noncancer pain (Table 18–5). The threestep
ladder encourages the use of more conservative
therapies before initiating opioid therapy. However, in
the presence of severe pain, the opioids should be considered
sooner rather than later.
Numerous societies and agencies have published
guidelines for the use of strong opioids in treating pain,
including the American Academy of Pain Medicine, the
American Pain Society, the Federation of State Medical
Boards (FSMB), and the Drug Enforcement Agency.
While slightly different in particulars, all guidelines to date
share the criteria established by the FSMB (Table 18–6).
Table 18–5
World Health Organization Analgesic Ladder a
Step 1 Mild to Moderate Pain
Non-opioid ± adjuvant agent
• Acetaminophen or an NSAID should be used, unless
contraindicated. Adjuvant agents are those that
enhance analgesic efficacy, treat concurrent
symptoms that exacerbate pain, and/or provide
independent analgesic activity for specific
types of pain.
Step 2 Mild to Moderate Pain or
Pain Uncontrolled after Step 1
Short-acting opioid as required ± non-opioid around
the clock (ATC) ± adjuvant agent
• Morphine, oxycodone, or hydromorphone should be
added to acetaminophen or an NSAID for maximum
flexibility of opioid dose.
Step 3 Moderate to Severe Pain or
Pain Uncontrolled after Step 2
Sustained release/long-acting opioid ATC or
continuous infusion + short-acting opioid as required ±
non-opioid ± adjuvant agent
• Sustained release oxycodone, morphine,
oxymorphone or transdermal fentanyl is indicated.
a
http://www.who.int/cancer/palliative/painladder/en/
Guidelines for the oral and parenteral dosing of
commonly used opioids are presented in Table 18–2.
Tables such as those presented here are only guidelines.
They are typically constructed with the use of
these agents in the management of acute (e.g., postoperative)
pain in opioid-naive patients. A number of
factors will contribute to the dosing requirement
(described in subsequent sections).
Methadone is considered separately in Table 18–7
as updated safety information has emerged more recently.
In 2006, the FDA notified health care professionals of
reports of death and life-threatening adverse events, such
as respiratory depression and cardiac arrhythmias in
patients receiving methadone. Methadone is thought to
be involved in about one-third of all prescription opioidrelated
deaths, exceeding hydrocodone and oxycodone,
despite being prescribed one-tenth as often. This has led
to revisions in the labeled dosing recommendations.
Variables Modifying the Therapeutic
Response to Opiates
There is substantial individual variability in responses
to opioids. A standard intramuscular dose of 10 mg
morphine sulfate will relieve severe pain adequately in
only 2 of 3 patients. The minimal effective analgesic
concentration for opioids, such as morphine, meperidine
(pethidine), alfentanil, and sufentanil, varies
among patients by factors of 5–10 (Woodhouse and
Mather, 2000). Adjustments will have to be made based
on clinical response. Appropriate therapeutics typically
involve undertaking a treatment strategy that most efficiently
addresses the pain state, minimizes the potential
for undesired drug effects, and accounts for the
variables that can influence an individual patient’s
response to opiate analgesia.
Pain Intensity. Increased pain intensity may require titrating doses
to produce acceptable analgesia with tolerable side effects.
Type of Pain State. Systems underlying a pain state may be broadly
categorized as being mediated by events secondary to injury and
inflammation and by injury to the sensory afferent or nervous system.
Neuropathic conditions may be less efficaciously managed by
opiates than pain secondary to tissue injury and inflammation. Such
pain states are more efficiently managed by combination treatment
modalities.
Acuity and Chronicity of Pain. The pain state in any given clinical
condition is not typically constant and will vary over time. In chronic
pain states, the daily course of the pain may fluctuate, e.g., being
greater in the morning hours or upon awakening. Arthritic states display
flares that are associated with an exacerbated pain condition.
Changes in the magnitude of pain occur during the daily routine
resulting in “breakthrough pain” during episodic events such as