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

played by the organ systems with which the receptors
are associated. Whereas the primary clinical use of
opioids is for their pain-relieving properties, opioids
produce a host of other effects. This is not surprising in
view of the wide distribution of opioid receptors in the
brain and the periphery. Within the nervous systems,
these effects range from analgesia to effects upon motivation
and higher-order affect (euphoria), arousal, and
a number of autonomic, hormonal, and motor
processes. In the periphery, opiates can influence a
variety of visceromotor systems, including those related
to GI motility and smooth muscle tone. The next sections
consider these class actions and their mechanisms.
Analgesia. In humans, morphine-like drugs produce analgesia,
drowsiness, changes in mood, and mental clouding.
When therapeutic doses of morphine are given to
patients with pain, they report the pain to be less intense
or entirely gone. Patients frequently report that the pain,
though still present, is tolerable and that they feel more
comfortable. In addition to relief of distress, some patients
may experience euphoria. A significant feature of the
analgesia is that it often occurs without loss of consciousness,
though drowsiness commonly occurs (see
“Respiration” later in the chapter). Morphine at these
doses does not have anticonvulsant activity and usually
does not cause slurred speech, emotional lability, or significant
motor uncoordination.
When morphine in an analgesic dose is given to
normal, pain-free individuals, the patients may report
the drug experience to be frankly unpleasant. There
may be drowsiness, difficulty in mentation, apathy, and
lessened physical activity. As the dose is increased, the
subjective, analgesic, and toxic effects, including respiratory
depression, become more pronounced.
Specificity of Analgesic Effects. The relief of pain by morphine-like
opioids is selective in that other somatosensory modalities, such as
light touch, proprioception, and the sense of moderate temperatures,
are unaffected. Systematic psychophysical studies have shown that
low doses of morphine produce reductions in the affective but not the
perceived intensity of pain whereas higher (clinically effective) doses
reduced both reported perceived intensity and the affective response
otherwise evoked by acute experimental pain stimuli (Price et al.,
1985). In general, continuous dull pain (as generated by tissue injury
and inflammation) is relieved more effectively than sharp intermittent
(incident) pain, such as that associated with the movement of
an inflamed joint, but with sufficient amounts of opioid it is possible
to relieve even the severe piercing pain associated with acute
renal or biliary colic.
Pain States and Mechanisms Underlying Different Pain States. Any
meaningful discussion of the action of analgesic agents must include
the appreciation that all pain is not the same and that a number of variables
contribute to the patient’s pain report and therefore to the effect
of the analgesic. Heuristically, one may think mechanistically of pain
as several distinct sets of events, described in the next sections.
Acute Nociception. Acute activation of small high-threshold sensory
afferents (Aδ and C fibers) generates transient input into the spinal
cord, which in turn leads to activation of neurons that project contralaterally
to the thalamus and thence to the somatosensory cortex.
A parallel spinofugal projection is to the medial thalamus and from
there to the anterior cingulate cortex, part of the limbic system. The
output produced by acutely activating this ascending system is sufficient
to evoke pain reports. Examples of such stimuli include a hot
coffee cup, a needle stick, or an incision.
Tissue Injury. Following tissue injury or local inflammation (e.g., local
skin burn, toothache, rheumatoid joint), an ongoing pain state arises
that is characterized by burning, throbbing, or aching and an abnormal
pain response (hyperalgesia) and can be evoked by otherwise
innocuous or mildly aversive stimuli (tepid bathwater on a sunburn;
moderate extension of an injured joint). This pain typically reflects
the effects of active factors (such as prostaglandins, bradykinin,
cytokines, and H + ions, among many mediators) released into the
injury site, which have the ability to activate the terminal of small
high-threshold afferents (Aδ and C fibers) and to reduce the stimulus
intensity required to activate these sensory afferents (peripheral
sensitization). In addition, the ongoing afferent traffic initiated by the
injury leads to the activation of spinal facilitatory cascades, yielding
a greater output to the brain for any given input. This facilitation is
thought to underlie the hyperalgesic states. Such tissue injuryevoked
pain is often referred to as “nociceptive” pain (Figure 18–4)
Tissue Injury
Local release of active
factors. (PG, BK, K)
Persistent activation/
sensitization of Aδ/C.
Activity in ascending pathways
+
spinal facilitation
Exaggerated output for
given stimulus input
Ongoing pain + Hyperalgesia
PG, BK, K
Sensitization
Injury
Facilitation
Figure 18–4. Mechanistic flow diagram of tissue injury–evoked
nociception.
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CHAPTER 18
OPIOIDS, ANALGESIA, AND PAIN MANAGEMENT