Download Acute Pain and Immune Impairment

®
PAIN
Clinical
Updates
INTERNATIONAL ASSOCIATION FOR THE STUDY OF PAIN®
Volume XIII, No. 1
March 2005
EDITORIAL BOARD
Editor-in-Chief
Acute Pain and Immune Impairment
Daniel B. Carr, MD
Internal Medicine, Endocrinology,
Anesthesiology
USA
V
Advisory Board
Elon Eisenberg, MD
Neurology
Israel
James R. Fricton, DDS, MS
Dentistry, Orofacial Pain
USA
Maria Adele Giamberardino, MD
Internal Medicine, Physiology
Italy
Cynthia R. Goh, MB BS, FRCP, PhD
Palliative Medicine
Singapore
Alejandro R. Jadad, MD, PhD
Anesthesiology, Evidence-Based
Medicine and Consumer Issues
Canada
Andrzej W. Lipkowski, PhD, DSc
Neuropharmacology and
Peptide Chemistry
Poland
Patricia A. McGrath, PhD
Psychology, Pediatric Pain
Canada
Mohammad Sharify, MD
Family Medicine, Rheumatology
Iran
Bengt H. Sjolund, MD, PhD
Neurosurgery, Rehabilitation
Sweden
Maree T. Smith, PhD
Pharmacology
Australia
Production
Elizabeth Endres, Copy Editing
Kathleen E. Havers, Executive Assistant
Juana Braganza Peck, Layout/Graphics
UPCOMING ISSUES
Pre-emptive Analgesia
Pain and Aging
Observations linking impaired postoperative
immune function to pain date back only 20 years.
Acute Pain and Immunity
Harriët M. Wittink, PhD, PT
Physical Therapy
The Netherlands
Visceral Pain
irtually all people and animals experience pain at some time in their lives.
The pervasiveness of pain makes it important to pursue observations of
potential immune dysfunction due to pain. These observations date back only
20 years, starting with reports from the laboratory of John Liebeskind that
footshock suppresses natural killer (NK) cell activity1 and promotes tumor
spread2 in the rat. Of relevance to the present survey (and discussed below) is
that both studies also showed that opioids compromise immune function and
promote tumor spread. Postoperative immune suppression had been documented
years before the footshock studies, but the observed immune suppression was not
attributed to perioperative pain. This issue of Pain: Clinical Updates reviews
current knowledge regarding the impact of acute pain and opioids on immune
function. It emphasizes the role of NK cells, a subpopulation of lymphocytes that
plays key roles in cell mediated immunity, the first line of immune defense. Without prior sensitization, NK cells recognize and kill a variety of virally infected or
neoplastic cells and initiate protection against some bacterial pathogens.3,4
Animal studies of the effects of experimental pain upon immune function
have employed stimuli such as footshock, tail shock, and surgery. In addition to
suppression of NK cell cytotoxic activity, pain from intermittent shock to the
foot or tail impairs proliferative responses of mononuclear or spleen cells to
mitogens5 and IgG antibody responses to novel antigen exposure.6
Animals recovering from surgery exhibit reduced splenocyte and lymphocyte proliferative responses to mitogens and suppressed NK activity.7,8 In
humans, similar evidence for widespread suppression of immune function
following surgery involves NK cell activity, lymphocyte responses to mitogen
stimulation, and cytokine secretion by immune cells.9,10 The magnitude of
immune suppression following surgery has been shown to be proportional to the
magnitude of the invasiveness of procedures in both animals11 and humans.12
Supported by an educational grant from Endo Pharmaceuticals Inc., USA
Many aspects of immune function in
preclinical and clinical studies are
impaired by acute nociception.
Is It the Pain?
Pain is an exquisite stressor. Because pain (among other
stressors) has both psychological and physiological components, to understand its effects it is necessary to clarify the relative contribution of each. One approach, used for over 30 years,
is to evaluate the impact of nonpainful stress on immunity.13,14
The linked responses of the central nervous system (CNS) and
the hypothalamic-pituitary-adrenal (HPA) axis to perceived
stress involve a complex network of neurosensory signals
including catecholamines, peptides such as endorphins, and
corticosteroids such as cortisol. There is bidirectional communication between the immune and neuroendocrine systems, each
affecting the other, as well as within-system interactions. Activation of the CNS and HPA axis affects immune function via
multiple mechanisms, and immune changes also impact these
two linked responses. Acute stressors such as public speaking,
time-pressured arithmetic, and school examinations have
consistently demonstrated suppression of NK activity and disruption of the balance of cell-mediated and humoral immune
activity.15
There is bidirectional communication between
the immune and neuroendocrine systems,
each affecting the other, as well as
within-system interactions.
The impact of a given stressor on immune function is
multidimensional and evolves over time. Single immune and
neuroendocrine measurements are snapshots at the time of sampling, and do not capture the dynamic nature of immune and
neuroendocrine responses to an event, nor their return to baseline. Techniques such as multiple blood samplings over time via
an indwelling catheter can provide a better picture, but for the
most part, blood and saliva samples have been reported at single
or infrequent time points after a stressor. Given the dynamic
nature of biological responses to stress, varying the sampling
time can give distinct apparent results with different underlying
explanations. For example, changes in aggregate NK activity
may equally well reflect a change in the cytotoxic activity per
NK cell or a change in the percentage of circulating NK cells.
Thus, a decrease in NK cell activity can be explained by either a
reduction in the activity per NK cell or a reduction in the number of circulating NK cells, or both. Among the first responses
to a stressor is activation of the sympathetic nervous system,
resulting in the release of catecholamines. During sympathetic
activation, white blood cell (WBC) subpopulations mobilize
from the marginating pool at stressor onset and then remarginate upon its resolution. Because β2-adrenergic receptors on NK
2
cells mediate suppression of their cytotoxic capacity,16 one
might observe varying levels of immune competency at different sampling times attributable to demargination and/or elevated
circulating levels of catecholamines. For example, sampling at
the time of peak NK cell concentrations might reveal an increase in NK activity attributed to the greater number of circulating NK cells. Indeed, such may be the case in a recent human
study that found electric shock to be NK-activity enhancing.17
Further complicating this picture in postoperative models
is the inevitable tissue damage and the associated release of
inflammatory mediators such as prostaglandins.18 For example,
prostaglandin E2 (PGE2) is a major contributor to both peripheral and central sensitization and hyperalgesia,19,20 but it also
suppresses NK activity21 and enhances production of interleukin
(IL)-6.22 Together with IL-1 and tumor necrosis factor (TNF)-α,
IL-6 promotes synthesis of acute phase proteins, induces fever,
and mobilizes energy stores. IL-6 also helps initiate local antimicrobial defenses, wound healing, and behavioral guarding of
the injury site via promotion of hyperalgesia.4 As the magnitude
of injury becomes increasingly severe, so dooes the magnitude
of these responses. The responses then may cease being homeostatic and can compromise survival following major trauma.23
Surgery, Pain, and Immunity in Humans
If pain is indeed a factor in postoperative immune impairment, then it is logical to surmise that more effective analgesia
could improve outcomes. Indeed, direct comparisons of inhalational versus epidural or spinal anesthesia for surgical procedures below the waist indicate that immune function is better
preserved with spinal nociceptive blockade.10,24 Epidural anesthesia and analgesia are associated with fewer postoperative
infectious complications25 than general anesthesia alone. In
contrast, studies of perioperative systemic opioid administration
have shown mixed results related to NK activity.
Clinical epidemiological studies suggest
that undertreated postoperative pain
compromises immune function.
A key function of NK cells is anti-tumor immunity.3 There
is substantial corroborating evidence in humans that NK function is important for cancer resistance. Decreases in NK activity
during the perioperative period are associated with greater rates
of cancer recurrence and mortality. Specific cancers for which
such relationships have been found include those of the breast,
head and neck, colon and rectum, and lung.26
Surgery, Immunity, and Cancer Metastasis in Animals
As opposed to observations in humans, which must rely on
epidemiology and correlations, animal studies provide convincing evidence for a causal link between low NK activity and
increased susceptibility to metastatic outcomes. Although no
animal model is a perfect reflection of the clinical metastatic
process, there are obvious, major ethical and methodological
obstacles to experimentally studying this phenomenon in
humans. Studies in animals using tumor lines whose growth is
modulated by NK cells have implications for understanding the
in vivo biological significance of this interaction.27 In wellestablished mouse and rat tumor models, animals given antibodies or drugs to reduce NK activity have more extensive and
aggressive metastases, while those given drugs to augment NK
activity appear relatively protected.
In well-established mouse and rat
tumor models, antibodies or drugs
that reduce NK activity promote
more extensive and aggressive metastases,
while drugs to augment NK activity
are relatively protective.
Not surprisingly, for a variety of tumor models in mice and
rats, the metastatic process is exacerbated by surgery and postoperative recovery. The earliest findings were documented in
1958.28 The first preclinical study to test the hypothesis that
perioperative analgesia influences postsurgical enhancement
of tumor growth was published 33 years later by Yeager and
Colacchio. They provided pre- and postoperative morphine to
rats undergoing and recovering from major abdominal surgery
and found that this regimen significantly reduced tumor burden
compared to saline-injected control animals.29 Since then, multiple reports have demonstrated a surgery-induced worsening of
metastatic outcomes, and its amelioration by systemic administration of the opioids morphine, fentanyl, and tramadol, and the
nonsteroidal anti-inflammatory drug (NSAID) indomethacin.
Additionally, spinal injection of a local anesthetic combined
with a very low dose of morphine also inhibited surgeryinduced increases in metastatic susceptibility. 27
Most of these studies employed experimental designs to
rule out some drug effect other than pain relief, such as a direct
impact on the tumor or on NK cells. A simple 2 x 2 design as
was used in the majority of studies (surgery versus no surgery,
by treatment versus no treatment) would exclude that possibility. Virtually all studies that used this design observed that drug
treatment improved tumor resistance only in the operated
animals, i.e., in the presence of postoperative nociception.
The spinal blockade findings also bolster the argument that
antinociception is essential for protection from the tumorenhancing effects of surgery.
In contrast, and paradoxically, another well-established
literature indicates that opioid administration suppresses
immune function and metastatic resistance. To reconcile that
literature with the strong experimental evidence for beneficial
effects of opioids on perioperative in vivo NK function and
tumor resistance, several points must be made. First and fore-
most is that opioids most clearly improve in vivo cancer resistance only in the context of postoperative nociception. Studies
that found deleterious immune and metastatic effects of opioid
administration tested normal animals under basal conditions.
Indeed, some non-operated control groups in studies of animals
undergoing surgery studies confirm that morphine administration in the absence of nociception results in a minor (generally
statistically insignificant) stimulation of tumor growth. Second,
the surgical studies used opioid doses in the analgesic range, but
most studies that found opioids to be immunosuppressive used
much higher doses than those necessary to produce analgesia.
Finally, several studies report behavioral observations consistent with postoperative pain relief from systemic opioids,
NSAIDs, or spinal anesthetics. Specifically, untreated animals
were inactive and inattentive to their environment soon after
abdominal surgery, while animals given systemic analgesics
exhibited activity levels that were not different from those of
unoperated animals.27
The beneficial effects of
perioperative opioid analgesia
upon immune function contrast with the
immune impairment seen when high doses
of opioids are given to unoperated animals
under baseline, resting conditions.
Conclusions and Implications
Strong evidence indicates that acute pain is an acute
stressor that impairs immune function, notably NK activity.
Given the key role played by NK cells in defending the
organism against viral and bacterial invasion, and inhibition
of tumor metastases, it would seem particularly important to
preserve immune capacity in those undergoing surgery.
Encouragingly, there is direct evidence in animals and indirect
evidence in humans that effective perioperative pain control
preserves perioperative NK function. Animal studies show that
optimal analgesic techniques provide significant protection
against the tumor-promoting effects of surgery, documenting an
important biological consequence of NK suppression. Although
animal findings cannot be directly applied to humans, existing
clinical evidence is consistent with these preclinical studies. In
aggregate, the evidence that poor pain control promotes tumor
growth after operations (especially in the case of individuals
with potentially metastasizing tumors) further strengthens
current humanitarian, ethical, economic, and physiological
arguments that perioperative pain relief is not simply a high
priority, but a fundamental human right.30
Strong evidence that uncontrolled pain
promotes tumor growth after operations
bolsters existing arguments that pain control
is a fundamental human right.
3
References
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
Shavit Y, et al. Science 1984; 223:188-190.
Lewis JW, et al. Nat Immun Cell Growth Regul 1983; 3:43-50.
Cerwenka A, Lanier LL. Nat Rev Immunol 2001; 1:41-49.
Janeway CA, et al. Immunobiology: The Immune System in Health
and Disease. New York: Garland Publishing, 1999.
Sacerdote P, et al. Brain Behav Immun 1994; 8:251-260.
Laudenslager ML, et al. Brain Behav Immun 1988; 2:92-101.
Nelson CJ, Lysle DT. J Surg Res 1998; 80:115-122.
Toge T, et al. Gann 1981; 72:790-794.
Akural EI, et al. Acta Anaesthesiol Scand 2004; 48:750-755.
Koltun WA, et al. Am J Surg 1996; 171:68-73.
Sandoval BA, et al. Am Surg 1996; 62:625-631.
Decker D, et al. Surgery 1996; 119:316-325.
Solomon GF, et al. Psychother Psychosom 1974; 23:209-217.
Lutgendorf SK, Costanzo ES. Brain Behav Immun 2003; 17:225-232.
Moynihan JA. Brain Behav Immun 2003; 17:S11-S16.
Schedlowski M, et al. J Immunol 1996; 156:93-99.
Greisen J, et al. Br J Anaesth 1999; 83:235-240.
Ben-Eliyahu S. Brain Behav Immun 2003; 17:S27-S36.
Martin HA, et al. Neuroscience 1987; 22:651-659.
Baba H, et al. J Neurosci 2001; 21:1750-1756.
Yakar I, et al. Ann Surg Oncol 2003; 10:469-479.
Williams JA, Shacter EJ. Biol Chem 2000; 272:25693-25699.
23.
24.
25.
26.
27.
Mack Strong VE, et al. Shock 2000; 14:374-379.
Le Cras AE, et al. Anesth Analg 1998; 87:1421-1425.
Yeager MP, et al. Anesthesiology 1987; 66:729-736.
Vallejo R, et al. J Environ Pathol Toxicol Oncol 2003; 22:139-146.
Page GG. Pain and immunosuppression. In: Schäfer M, Stein C (Eds.)
Mind Over Matter—Regulation of Peripheral Inflammation by the CNS. Basel:
Birkhäuser Verlag, 2003, pp 57-68.
28. Lewis MR, Cole WH. Arch Surg 1958; 77:621-626.
29. Yeager MP, Colacchio TA. Arch Surg 1991; 126:454-456.
30. Brennan F, Cousins MJ. Pain: Clin Updates XII(5).
Gayle G. Page, RN, DNSc, FAAN
School of Nursing
Johns Hopkins University
525 N. Wolfe St.
Baltimore, MD 21205, USA
Tel: 410-614-6281
Fax: 410-614-1446
Email: [email protected]
Erratum
In Volume XII, No. 7 of Pain: Clinical Updates, entitled “Anxiety and Pain,” the word “pain” should be changed to “analgesic
pharmacotherapy” and the word “anxiety” should be changed to “psychopharmacology” in Figure 1. The legend should read:
“Overlapping circles emphasize the concordance between analgesic pharmacotherapy and psychopharmacology.”
IASP was founded in 1973 as a nonprofit organization to foster and encourage research on pain mechanisms and pain syndromes, and to help
improve the care of patients with acute and chronic pain. IASP brings together scientists, physicians, dentists, nurses, psychologists, physical therapists, and other health professionals who have an interest in pain research and treatment. Information about membership, books, meetings, etc., is
available from the address below or on the IASP Web page: www.iasp-pain.org. Free copies of back issues of this newsletter are available on the
IASP Web page.
Timely topics in pain research and treatment have been selected for publication but the information provided and opinions expressed have not
involved any verification of the findings, conclusions, and opinions by IASP. Thus, opinions expressed in Pain: Clinical Updates do not necessarily
reflect those of IASP or of the Officers or Councillors. No responsibility is assumed by IASP for any injury and/or damage to persons or property as
a matter of product liability, negligence, or from any use of any methods, products, instruction, or ideas contained in the material herein. Because of
the rapid advances in the medical sciences, the publisher recommends that there should be independent verification of diagnoses and drug dosages.
For permission to reprint or translate this article, contact:
International Association for the Study of Pain, 909 NE 43rd St., Suite 306, Seattle, WA 98105-6020 USA
Tel: 206-547-6409; Fax: 206-547-1703; email: [email protected]; Internet: www.iasp-pain.org and www.painbooks.org
Copyright © 2005, International Association for the Study of Pain®. All rights reserved. ISSN 1083-0707.
4
Printed in the U.S.A.