DEVELOPMENT OF TOLERANCE TO OPIATES

Dear Forum,

I came across this discussion about tolerance. Tolerance is when
your painkiller does not work anymore. It's something we all get to
face someday, sooner or later, enjoy!


SPECIAL ISSUE: DEVELOPMENT OF TOLERANCE TO OPIATES

INFLUENCE OF PRIOR MORPHINE EXPOSURE

Tolerance develops more quickly in animals previously exposed to
morphine. Experimental rats (group E) were treated with 10 µg morphine
twice daily intrathecally (i.t.) for three 7-day cycles, separated by
7-day rest periods, while controls (group C) received saline i.t. The
tail flick test was used to assess the degree of morphine-induced
analgesia. Group E rats demonstrated complete morphine tolerance by day
7 of the first cycle, day 5 of the second, and day 3 of the third, with
preservation of morphine-induced analgesia for the initial dose of the
second and third cycles. Group C showed no change. The expression of
glucocorticoid receptors (GR) in the dorsal horn of Group E rats was
markedly increased by day 3 of the first cycle (P<0.05). Furthermore,
GR upregulation was still present at the end of the first 7-day rest
cycle, to an even greater degree than at the end of the 7 days of
morphine exposure (P<0.05), and it was elevated to an even greater
degree at corresponding time points of the second cycle of morphine
exposure (P<0.05). Blockade of glucocorticoid receptors, the use of
adrenalectomized rats, or the infusion of antisense oligonucleotides
all abolished the development of tolerance in this model. Potential
clinical implications of these findings are clearly discussed. (Lim G,
et al. Pain. 2005;114:81-92)

INFLUENCE OF PROINFLAMMATORY CYTOKINES

Series of experiments in mice indicate interleukin-1ß (IL-1ß) may be
responsible for acute tolerance to morphine. The antianalgesic effect
of IL-1 and the corresponding potentiation of analgesia by blockade of
IL-1ß signaling were clearly shown in an initial series of experiments
with mice. Thermal pain was tested with the hot-plate test and
mechanical pain with the von Frey filament test. When a neutral dose of
IL-1ß (ie, a dose with no intrinsic analgesic or antianalgesic effect)
was administered, the analgesic effect of morphine (10 mg/kg s.c.) was
abolished (P<0.01). In transgenic mice with over-expression of IL-1
receptor antagonist, morphine analgesia was potentiated, compared with
wild-type controls (P<0.0001). Similar experiments showed that IL-1
blockade increased the time span of effective morphine analgesia up to
270 min vs 30 min in controls (P<0.005). The potency of morphine
analgesia was also increased, with a subtherapeutic dose of 1 mg/kg
s.c. producing analgesia at 30 min in mice with impaired IL-1 signaling
vs no analgesia in controls (P<0.0001). In the next set of
experiments, mice with impaired IL-1 signaling (3 different transgenic
strains) and wild-type controls were injected with morphine (10 mg/kg
s.c.) twice daily for 5 days. By day 3, the controls had a reduced
analgesic response to morphine (both testing paradigms), whereas mice
with impaired IL-1 signaling showed no signs of tolerance, even at day
5 (P<0.0001). This finding was replicated in mice treated chronically
with IL-1 receptor antagonist, who showed no tolerance to morphine
analgesia over 10 days using the same experimental paradigm. Thus, IL-1
signalling has a potent antagonistic effect on morphine-induced
analgesia and may be a therapeutic target in the treatment of pain.
(Shavit Y, et al. Pain. 2005;115:50-59)

INFLUENCE OF AGE

Dose and response patterns of older vs younger patients show distinct
differences. In this retrospective chart review of patients who were
treated for nonmalignant chronic pain (mean duration, 8.2 yr) with
long-acting opioids in a multidisciplinary pain treatment program, a
sample of 104 young patients =50 yr (Y) and 102 elderly patients
=60 yr (E) was obtained. Pain diagnoses, opioid dosages (initial,
peak, and final, in morphine equivalents), and VAS pain scores for each
patient were identified. Despite equivalent initial pain scores (Y,
8.4; E, 8.3), opioid dosages (Y, 49 ± 3 mg/d; E, 42 ± 3 mg/d), and
time span of dose escalation from initial to peak dose (Y, 15.0 ± 1.3
mo; E, 14.4 ± 1.5 mo), the mean peak dose in Y was 452 ± 63 mg/d vs
211 ± 23 mg/d in E (P<0.0001) and the final dose (at ~27 mo) was 365
± 61 mg/d in Y vs 168 ± 18 mg/d in E (P<0.0001). In addition, there
was no difference in VAS scores in Y between preopioid baseline and
final visit (6.2 ± 0.3 vs 6.1 ± 0.3, P=NS), whereas in E there was
(6.9 ± 0.3 vs 5.6 ± 0.3). Although alternative explanations are
possible, and the limits of a retrospective study are clear, these data
support the hypothesis that tolerance to opioids develops more slowly
and less completely in older adults than in younger ones.
(Buntin-Mushock C, et al. Anesth Analg. 2005;100:1740--1745)

Dramatic age-related differences in the development of tolerance
demonstrated in rats. Morphine administered to rats twice daily (8
mg/kg s.c.) produced complete analgesia, as measured by tail-flick
latency to a thermal stimulus. Rats of 4 different ages--3 weeks (3w),
3 months (3m), 6 months (6m), and 1 year (1y)--were tested 5 min
before and 30 min after each morphine injection. Tolerance was defined
as the point at which tail-flick latency was no longer significantly
different from the day 1 baseline value and at least 75% of day 1
analgesia was lost. A linear correlation between age and tolerance was
found, occurring at day 4 in the 3w group, day 10 in the 3m, day 14 in
the 6 m, and day 22 in the 1y. Measures of morphine and metabolite
levels did not show any pharmacokinetic changes that correlated with
the development of tolerance. This striking relationship between older
age and slower development of tolerance in this animal model lends
further support to the clinical findings noted above. (Wang Y, et al.
Anesth Analg. 2005;100:1733-1739) Editorial comment. The authors of
the editorial highlight some of the limitations of each of the 2
studies cited while acknowledging their importance and the need for
further research in this area. (Agin CW, Glass PSA. Anesth Analg.
2005; 100:1731-1732)

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