As of late I have read a lot of research with hyperalgesia as a causative of too high of dosage of opioids. When more dubious research is involved factors such as genotype, sex (male/female) parental exposure, drug, dosage, method of introduction, synthetic vs. organic, agonist only vs. agonist with antagonist components, poor diet coupled with alcoholism, foliate, vitamin 12 deficiency are just a few intervening variables.
The simplicity with which the researchers for the "Labor and Industries" in the State of Washington headed by Dr. Gary Franklin, who have suggested capping opioid intake on a daily level to 120 mgs. of morphine or equivalent could cause chaos throughout the Intractable Chronic Pain Community, forcing pain patients to alcohol for pain abatement, or worse to the streets and into the criminal system who would otherwise be no more then people in severe pain who have had their pain meds cut down to an intolerable amount or lack there of, to compensate for a "one size fits all prescription" for a multitude of highly complex syndromes based in complex biochemistry and psychopharmacology such as the following research addresses in a much needed fashion. Hyperalgesia and opioid tolerance can be miss-addressed in much the same fashion, with the same harmful effects to the patient. I suggest "First do no harm."
As of Feb 2008 OIH (opioid induced hyperanalgesia ) has only been shown in animal subjects.(1)
® Feb 2008
The following study also brings up some serious reservations and serious consequences to the simplistic approach to simply capping the amount of daily opioid dosage.

Preemptive Antihyperalgesia to Improve Preemptive
BASED on the rationale that gabapentin effectively treats
neuropathic pain and that there are many similarities in
mechanisms between neuropathic pain and hyperalgesia
from opioid administration,
1 Van Elstraete et al.2 tested
whether gabapentin could also reduce hyperalgesia induced
by a short-term use of fentanyl in rats, and reported
in this issue of A
NESTHESIOLOGY that it was effective,
although no analgesic effect
per se was observed. These
observations agree with a recent study in human volunteers
showing that pregabalin, a gabapentin analog, has
no effect on electrically evoked pain but significantly
reduces the areas of punctuate mechanical hyperalgesia.

Numerous experimental and clinical studies suggest
that gabapentin is unlikely to be a conventional analgesic
and may have a selective effect on pain processes involv-

This Editorial View accompanies the following article: Van
Elstraete AC, Sitbon P, Mazoit J-X, Benhamou D: Gabapentin
prevents delayed and long-lasting hyperalgesia induced by
fentanyl in rats. A
NESTHESIOLOGY 2008; 108:484–94.

Accepted for publication December 7, 2007. The author is not supported by,
nor maintains any financial interest in, any commercial activity that may be
associated with the topic of this article.

Anesthesiology, V 108, No 3, Mar 2008
ing central sensitization, such as that which occurs with
opioid exposure. This result highlights new ways of thinking
to improve the management of postoperative pain.
Although opioids are well recognized as unsurpassed
analgesics for relieving moderate to severe pain, clinical
studies have reported for more than a century that hyperresponsiveness
to noxious stimuli is the most common
symptom of withdrawal after prolonged opioid
administration. More recently, the paradoxical phenomenon
of opioid-induced hyperalgesia (OIH) has been
described to develop rapidly after a single opioid exposure
in animals, human volunteers, and surgical patients.

OIH is now recognized to reflect a sustained sensitization
of the nervous system in which excitatory aminoacid
neurotransmitter systems play a critical role, especially
via N
-methyl-D-aspartate (NMDA) receptors. From
a medical viewpoint, abnormal persistence of excitatory
neuroplasticity is now considered to be a major, if
largely unrecognized, candidate mechanism for the development
of chronic pain.
5 One hypothesis is that the
administration of large doses of opioids, as used for
surgery in humans, increases the risk to induce not only
early exaggerated postoperative pain, but also the development
of postoperative chronic pain. This does not
mean that opioid use must be eliminated for surgical
analgesia in humans (certainly not!) but provides yet
another rationale to reduce opioid dose to avoid unidentified
and then unevaluated long-lasting deleterious effects
on pain sensitivity. Moreover, therapies that can
oppose early postoperative hyperalgesia and reduce
postoperative opioid consumption should be developed,
because these are perhaps linked phenomena. Several
points should be considered.
From a mechanistic viewpoint, experiments in animals
and human volunteers show that drugs that affect NMDA
receptor functioning directly, such as NMDA receptor
antagonists like ketamine, memantine, dextromethorphan,
magnesium, or nitrous oxide, or indirectly by reducing the
spinal release of excitatory amino acid neurotransmitters,
such as the cyclooxygenase inhibitors, prevent OIH by
inhibiting an overactivation of pronociceptive systems
and antiopioid systems that directly oppose the analgesic
effects of opioids.
5 Gabapentin acts via different mechanisms
than NMDA receptor antagonists or cyclooxygenase
inhibitors because it presynaptically binds to the

21 subunit of voltage-gated calcium channel (Cav21).
Elevated Ca
v21 at the spinal cord level has been proposed
to contribute to pain hypersensitivity in neuropathic
pain models.
6 Interestingly, gabapentin effects on
voltage-gated calcium channel currents are minimal in
wild-type mice as compared with significant inhibition in
transgenic mice that constitutively overexpress Ca

in neuronal tissues.
7 Voltage-gated calcium channel current
blockade by pregabalin leads to a decrease of release
of the excitatory neurotransmitters substance P
and glutamate, which are themselves known to be involved
in pain hypersensitivity. One hypothesis (which
does not exclude other mechanisms) is that gabapentin
indirectly prevents OIH
via inhibition of overactivation
of NMDA receptors like other antihyperalgesic drugs.
However, an up-regulation of neuronal Ca
v21 in this
OIH experimental model has not been investigated.
When this information is taken together, it is conceivable
indirect modulation of NMDA receptor functioning
by gabapentin is more useful clinically than direct receptor
blockade by NMDA receptor antagonists for opposing
OIH because side effects are more limited with the
former approach. This is also supported by our recent
observation that a polyamine-deficient diet, which negatively
modulates overactivation of NMDA receptors

an NMDA allosteric polyamine site, is an efficacious
strategy devoid of any noticeable side effects to relieve
pain hypersensitivity.

From a therapeutic viewpoint, these data could lead us
to reevaluate preemptive analgesia. Preemptive analgesia
is defined as a treatment initiated before the surgical
procedure to prevent pain and sensitization. Numerous
clinical studies indicate that the level of preoperative
pain is correlated with the development of early postoperative
pain and with the subsequent development of
chronic pain, which may persist for months or years
after surgery. Indeed, even though the best way to prevent
pain sensitization might be to block completely any
pain signal originating from the surgical wound from the
time of incision (or opioid administration) until final
wound healing, it is noteworthy that analgesic drugs
used for surgery have different pharmacologic profiles.
Therefore, opioids, though potent analgesics, are typically
“false friends” for preemptive analgesia because
they also induce delayed and long-lasting pain hypersensitivity.
As indicated by Eisenach
9 in an Editorial View in
this journal, opioids might induce “Preemptive hyperalgesia,
not analgesia.” Indeed, the study by Van Elstraete

et al.
2 and related OIH studies suggest that analgesia is
necessary but not sufficient to develop good preemptive
analgesia and that a preemptive antihyperalgesic is also
needed. Among available therapies, the early administration
of antihyperalgesic agents that are not antinociceptive

per se
, such as gabapentin; polyamine-deficient diet;
or analgesics with specific antihyperalgesic properties,
such as buprenorphine, nitrous oxide, cyclooxygenase
inhibitors, or nefopam might be fruitful strategies for
improving preemptive analgesia. These agents may be
also preferentially used during the postoperative period
to reinforce this antihyperalgesic strategy.
Finally, from a medical viewpoint, patients with high
intensity of early postoperative pain are known to have
a higher risk of developing a chronic pain state.
5 Opioids
might reinforce this deleterious phenomenon. Experimental

and clinical studies
11 indicate that preoperative
and perioperative therapies that are efficacious to prevent
early exaggerated postoperative hyperalgesia also


Anesthesiology, V 108, No 3, Mar 2008
oppose long-lasting pain hypersensitivity,
i.e., pain vulnerability.
This phenomenon, which is paradoxically facilitated
by opioids, has been referred to as a “latent pain
10 because it may aggravate preexisting
pain that could have gone unnoticed in the absence of
subsequent nociceptive inputs. Gabapentinoids have
demonstrated promising antihyperalgesic potential in a
number of clinical trials of early postoperative pain.
However, the ability of gabapentin to prevent the development
of postoperative chronic pain must be evaluated
in combination with different classes of “traditional”
analgesics. Indeed, we must reevaluate analgesics, especially
opioids, independently of their own analgesic potencies
because OIH studies indicate that certain opioids,
especially fentanyl and remifentanil, induce hyperalgesic
effects, whereas others, such as buprenorphine or methadone,
exert a lasting antihyperalgesic effect.
12 Attempting
to combine preemptive analgesia with preemptive
antihyperalgesia could be a fascinating challenge for
modern anesthesiology because chronic pain occurs in
10–50% of patients after surgery, especially when it is
associated with nerve injury. Other therapies, such as
continuous local anesthetic wound infusion or systemic
antiinflammatory corticosteroid therapy, might reinforce preemptive
antihyperalgesia. Although the possibilities are exciting,
application of such therapeutic strategies will also
need to apply Hippocrates’ dictum,
primum non nocere
first, do no harm.

Guy Simonnet, Ph.D.,
Universite Victor Segalen-Bordeaux 2,
Universite´ Bordeaux 1, Centre National de la Recherche Scientifique,
Unite´ Mixte de Recherche 5227, Home´ostasie-Allostasie-Pathologie-
Re´habilitation, Bordeaux, France.

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2008; 108:484–94
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Anesthesiology 2008; 108:354–6 Copyright © 2008, the American Society of Anesthesiologists, Inc. Lippincott Williams & Wilkins, Inc.