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The Oxygen View of Pain
THE OXYGEN VIEW OF PAIN:
EVERY CHRONIC PAIN IS SOME CELLS' CRY FOR OXYGEN
Majid Ali, M.D.
Oxygen is the organizing influence of human biology and governs the aging
process. In 2000, I began
Oxygen and Aging1 with those words. Oxygen is a master work of nature an
enduring tribute to Nature's preoccupation with complementarity and contrariety.
It is an elixir of life and a hemlock for death the ultimate molecular Dr.
Jekyll and Mr. Hyde. Sometimes by its presence and sometimes by its absence,
oxygen initiates signaling for cellular life as well as demise. In that context,
it is important to recognize that oxygen drives chronic pain pathways primarily
by its absence.
A large number of pain neurotransmitters are involved in clinical pain
syndromes, including: substance P; enkephalins; neurokinin 1, 2, and 3;
serotonin; adenosine triphosphate (ATP); nitric oxide; calcitonin; vasoactive
intestinal peptides; epinephrine, norepinephrine, and related sympathomimetic
agents; glutamic acid, aspartic acid, and related excitatory transmitters; and
GABA, glycine, and related inhibitory transmitters.2-4 Some excitatory
transmitters concerned with chronic pain include glutamic acid and aspartic
acid, which are involved with dorsal horn sensitization through activation of
NMDA receptors, while inhibitory transmitters participate in mechanisms that
prevent or diminish pain. It seems safe to predict that future work will
establish that, directly and indirectly, all those molecular species are
triggered or influenced by oxygen deficit.
Oxygen and Pain Neurotransmitters
Neurotransmitters transmit information across synapses regions separating
neurons from adjoining neurons, as well as neurons from the muscle cells. These
substances are stored in the bulbous ends of axons, and are released by
electrical impulses traveling along the nerves to those ends. Upon their
release, neurotransmitter either facilitate or inhibit continued electrical
impulses along the nerve fibers on the other side of the synapse. Over 300
molecular species have been recognized to be involved in neurotransmission.5
Some of the best known of those over 300 neurotransmitters have been listed in a
preceding section. It is regrettable that all neurologists and others in the
headache industry I know limit their work only to serotonin and a few related
neurotransmitters.
Next to oxygen and serotonin, substance P (SP) is the best examined of all the
pain neurotransmitters, and its relationship with oxygen deficit has been most
clearly delineated.6-11It is an 11-residue peptide belonging to the tachykinin
sub-family of G-protein-coupled receptors (GPCR). Those receptors form a class
of integral membrane proteins. Serotonin in the mammalian brain and receptors of
the olfactory epithelium that binds odorants are two other members of this
family are receptors.
Oxygen deficit triggers the release of substance P. There are several lines of
direct and indirect evidence for it.12,13 Direct evidence for that comes from
experiments in which decreasing concentrations of oxygen were associated with
the release of increasing amounts of SP.12 Specifically, the carotid bodies
contain SP in concentrations ranging from 1.4 to 1.6 ng/mg protein that is
released in response to tissue hypoxia. The amount of SP released from the
carotid bodies increases in proportion to the severity of hypoxia. It is
noteworthy that the release of SP by hypoxia is a calcium-dependent process, and
is primarily mediated by N- and L-type Ca2+ channels.13
Other lines of evidence for the fundamental role of oxygen deficit in the
causation of pain include the following: (1) skin lactate levels are increased
in complex regional pain14; (2) SP increases protein extravasation in regional
chronic pain states15; (3) intradermal injection of epinephrine causes local
pain (due to vasoconstriction and consequent oxygen deficit)16; (4) a tissue
hypoxia occurs in complex regional pain syndrome17; (5) ascorbic acid reduces
pain in reflex sympathetic dystrophy18; and (6) certain other free radial
scavengers also reduce pain in complex regional pain states19 the mechanism of
action of antioxidants being restoration of local oxygen homeostasis.
Substance P exerts varied effects on different tissues.20-24 It is excitatory to
the carotid body. Release of larger amounts of SP in the lungs is associated
with pulmonary hypertension, an effect that is attenuated by antioxidants. In
the nasal mucosa, hyperbaric oxygen decreases immunoreactivity to substance P.25
Not unexpectedly in light of the oxygen/SP dynamics, oxyradicals under certain
conditions also trigger the release of substance P. By contrast, antioxidants,
such as ascorbic acid, inhibit the release of SP.18 However, the relationships
between antioxidants and SP are complex. For instance, ca
icin increases
regional perfusion and oxygen delivery, inhibiting the release of SP but is
also known to increase SP release in the lung. Oxidants also have complex
relationships with SP. For example, nitric oxide serving as an oxidant modulates
histamine release from tissue mast cell and circulating basophils, and so
contributes to pain caused by histamine.26-27 On the other hand, nitric oxide,
through its vasodilator role, improves oxygen transport, decreases the release
of SP, and mitigates some pain syndromes. (See Nature's Preoccupation With
Complementarity and Contrariety, the first volume of The Principles and Practice
of Medicine,28 for an in-depth treatment of the subject).
Substance P also has complex relationships with certain other physiologic
compounds, including enzymes and hormones.29,30 For instance, increased amounts
of erythrocyte 2,3-diphosphoglycerate (2,3 DPG) caused by chronic hypoxia is
associated with increased release of SP. Since chronic hypoxia increases the
concentration of 2,3-DPG, this provides yet another mechanims by which oxygen
deficit causes pain. Fascinating! How oxygen, by its absence, both triggers a
mechanism for correcting that problem (by increasing 2,3-DGP production) and
sends out messages to other cellular systems for participation in that effort
(by inducing the production of SP). An example of the involvement of enzyme
system with SP is that acute depressor actions of angiotensin II in the nucleus
of the solitary tract are mediated by SP. An insight into the possible
interactions between SP and hormones is provided by the complementary roles of
SP and calcitonin gene-related peptide in the causation of phantom and ischemic
pains.
An interesting aspect of the oxygen/substance P dynamics is revealed by the case
of the East African naked mole-rats (Heterocephalus glaber). This rat species
lacks substance P and does not appear to suffer pain when tormented.31 The rats
feel no immediate pain when cut, scraped or subjected to heat stimuli. They only
feel some aches. But when the rats get a shot of SP, pain signaling resumes
working as in other mammals. One can only wonder about what other defense
mechanisms exist in this rat species that compensate for substance P.
On the Nature of Pain
Pain is a sensory perception intricately linked to the emotional state of the
person. Pain is not a disease, nor a discrete bodily state. That explains why
pain in different cultures means different things to different people. This is a
crucially important aspect of pain when considering the biochemistry of pain
neurotransmitters presented above. I had certain ideas of pain during three
decades of my work as a surgeon and a pathologist. In those years, I suffered
migraine attacks. Since vomiting accompanying migraine did not allow me to keep
any painkillers down, I gave myself Demerol injection for relief. My work in
integrative medicine changed all that. Then I taught myself control of migraine
by assuring optimal hydration, preventing rapid hypoglycemic/hyperglycemic
roller coasters and consequent rapid insulin shifts, addressing issues of mold
and food allergy, and controlling vasospasm with self-regulatory methods all
measures that restore oxygen homeostasis, locally or systemically. I have not
had to take Demerol during the last eight years. I have a prolapsed lumbar disc
which sometimes caused disabling backache. During those years, I also taught
myself control of that pain with limbic breathing32 an energetic method of
breathing with extended periods of exhalation (see Healing Miracles and the Bite
of the Gray Dog33 for details of other effective self-regulatory methods). For
years, I have controlled my back pain with limbic breathing, without any
painkillers, manipulations, laser or other therapies.
I might point out here that direct oxygen therapies oxygen by mask and
hyperbaric oxygen have been successfully used in controlling headaches and
migraine attacks.34-37 Specifically, in one double-blind trial breathing 100%
oxygen for 15 minutes or less during headache episodes controlled or
significantly reduced the pain of acute cluster attacks in all subjects.34 Not
surprisingly, one fourth of the study participants experienced cluster attacks
soon after the treatment was stopped35 since various elements putting in
jeopardy oxygen homeostasis were not addressed. Administration of higher
concentrations of oxygen during the postoperative period relieves or reduces the
intensity of postoperative pain. It appears to both reduce the release of
substance P and influence pain inhibitory pathways in the peripheral nerves.
Correlation between urinary substance P and bladder pain has been documented.
Seeing Pain, Thinking Oxygen
In my clinical work when I see pain, I think oxygen. I think about how
dehydration in one person worsens functional oxygen deficits, and how
incremental oxidative stress threatens oxygen homeostasis locally and/or
systemically in another. I think about how hyperglycemic- hypoglycemic shifts
trigger rapid insulin responses increases the intensity of pain in yet others. I
think about how undetected and unmanaged allergic triggers acting in the bowel
and elsewhere cumulatively cause oxidosis, acidosis, dehydration, add to
oxidosis, acidosis and then all collectively threaten functionality of oxygen,
increasing the degree of pain regardless what the initial pain triggers might
be. Then I wonder how often do neurologists and anesthesiologists at pain
centers think about the effects of total body burden of toxic metals and
xenobiotics on pain neurochemistry by feeding the frenzy of the three furies
of pain oxidosis, acidosis, and
dysoxygenosis.
Following are some commonly observed clinical manifestations of biochemical
interactions among the pain sensors and modifiers listed above:
1. Coronary chest pain is relieved or mitigated by the administration of oxygen,
as are attacks of headache and migraine34-37;
2. Direct oxystatic measures treatments that restore oxygen homeostasis,
including ozone, hydrogen peroxide, singlet oxygen, and related treatments
prevent, diminish or relieve diffuse tissue pain in
fibromyalgia38,39;
3. Indirect oxystatic measures treatments such as prolotherapy with injection
of 50% glucose or other suitable agents that stimulate fibroproliferative
responses relieve trigger point pain by evoking local oxystatic inflammatory
tissue response40;
5. Chronic back pain in many cases can be relieved by effective self-regulatory
methods, especially with specific breathing methods (see limbic breathing in The
Cortical Monkey and Healing32;
6. Pain syndromes accompanying reflex sympathetic dystrophy can be relieved with
direct oxystatic therapies combined with indirect oxystatic measures, including
restoration of bowel ecology and hepatic detoxification (personal unpublished
observations); and
7. Cooling of forehead diminishes sympathetic tone, increases regional blood
supply (correcting oxygen deficit), and relieves certain types of pain
associated with dysautonomia.41
On deeper reflection, the pain-relieving roles of oxygen and oxyradicals can be
recognized in most, if not all, empirically proven pain control therapies.
Indeed, in my own clinical work I find that every chronic pain can be partially
or completely controlled by effective direct and indirect oxystatic therapies.
That, in essence, is the "oxygen view of pain" presented in this article.
Author's Priorities for Headache and Migraine: A Clinical Application of the
Oxygen View of Pain
Headache and migraine patients must take the time to understand the true nature
of their suffering, and not waste time on worrying what type of headache and
migraine they may or may not have. They must understand that drug therapies
cannot be accepted as the full treatment of their suffering. They must know that
their suffering can be prevented by non-drug therapies, except in rare instances
of pain associated with depression, anxiety, or drug dependence. It is mandatory
to have tests done for antibodies for molds and this issue addressed. Mold
sensitivity was present in nearly all of my patients with headache attacks. The
same holds for uncovering and effectively managing food sensitivities. Even
ordinary fluctuations in blood sugar levels can trigger headache attacks. So
headache and migraine patients must not miss breakfast. Similarly, dehydration
increases vulnerability to headache, and optimal hydration must be assured for
optimal control of headache. In many instances, myofascial trigger points in the
neck, shoulders, and scalp trigger headache attacks. Such trigger points require
resolution by appropriate therapies. The author's choice is prolotherapy with
50% glucose.40 Headache and migraine patients must become sensitive to problems
caused by excess acidity.
Cellular oxidosis, acidosis, and dysoxygenosis resulting from nutrient deficits
can trigger, perpetuate, or intensify headache. So, I consider nutritional
therapies magnesium, calcium, and potassium stand out in this context as
well as selected phytotherapies as important components of the program. And most
importantly, headache and migraine attacks are commonly triggered by stress and
perpetuated by chronic anger. Thus, such patients must learn effective
self-regulatory methods for prevention and treatment of headache. (See Healing
Miracles and the Bite of the Gray Dog.23) Most importantly, persons with
headache and migraine must learn to think oxygen when they experience pain. They
need to recognize that self- regulatory, nutritional, and environmental measures
enlighten and empower them, while drug therapies for headache disempower the
sufferers and keep them in the dark.
In closing, the crucial clinical importance of the "oxygen view of pain"
presented above is this: It mandates that all relevant oxygen issues be
diligently addressed in the clinical management of every patient with a chronic
pain syndrome. How often do clinicians recognize the essential commonality of
biochemical lesions oxidosis, acidosis, and dysoxygenosis that cause
migraine and heart attack? How often do they see that commonality between the
pain episodes of severe dysmenorrhea and myofascial trigger points? And that
between arthritis and sympathetic reflex dystrophy? And that between pain of
prolapsed vertebral discs and fibromyalgia? And that between pain of TMJ and
renal colic? The oxygen view of pain provides a clear link. What might be
required for managing ischemic coronary syndromes with the oxygen view of pain?
The same approach as for controlling migraine attacks given above. Why? Because
the oxygen issues that cause oxidative coagulopathy and so set the stage for
coronary artery blockages are exactly the same as those that trigger migraine
attacks.
Cholesterol, I might add here, is an antioxidant and protects the
coronary arteries until it gets oxidized, becomes rancid, contributes to
oxidative coagulopathy, and sets the stage for atherosclerosis.
References
1. Ali M.
Oxygen and Aging. (Ist ed.) 2000. New York, Canary 21 Press. Aging
Healthfully Book 2000.
2. Darnell J, Lodish H, Baltimore D. Molecular Cell Biology. 1990. New York.
Scientific American Books. Distribted by WH Freeman and Company. pp 784-802.
3. Katz B. Nerve, Muscle, and Synapse. 2nd. ed. 1966. New York. McGraw-Hill.
4. Salerno, Evelyn, and Joyce S. Willens, eds. Pain Management Handbook: An
Interdisciplinary Approach. St. Louis: Mosby, 1996.
5. Verbunt J, Seelen H, Vlaeyen J, et al. Disuse and deconditioning in chronic
low back pain: concepts and hypotheses on contributing mechanisms. Eur J Pain
2003;7:9-21.
6. Krause JE, Takeda Y, Hershey AD. Structure, functions, and mechanisms of
substance p receptor action. J Invest Dermatol. 1992;98:2S-7S.
7. Pernow B. Substance P. Pharmacol Rev. 1983;35:85-141.
8. Bolton TB, Clapp LH. Endothelial-dependent relaxant actions of carbachol and
substance p in arterial smooth muscle. Br J Pharmacol. 1986;87:713-723.
9. Diz DI, Fantz DL, Benter IF, Bosch SM. Acute depressor actions of angiotensin
II in the nucleus of the solitary tract are mediated by substance P. Am J
Physiol. 1997;273:R28-R34.
10. Tagawa T, Mohri M, Tagawa H, Egashira K, Shimokawa H, Kuga T, Hirooka Y,
Takeshita A. Role of nitric oxide in substance p-induced vasodilation differs
between the coronary and forearm circulations in humans. J Cardiovasc Pharmacol.
1997;29:546 -553.
11. Naoko Kanda and Shinichi Watanabe . Substance P Enhances the Production of
Interferon-induced Protein of 10 kDa by Human Keratinocytes in Synergy with
Interferon- Journal of Investigative Dermatology 119, 1290-1297 (2002)
12. Kim DK, Oh EK, Summers BA, Prabhakar NR, Kumar GK. Release of substance P by
low oxygen in the rabbit carotid body: evidence for the involvement of calcium
channels. Brain Res. 2001 Feb 23;892(2):359-69.
13. Chen MJ, Chiang LY, Lai YL. Reactive oxygen species and substance P in
monocrotaline-induced pulmonary hypertension. 1: Toxicol Appl Pharmacol.
2001;171:165-73.
14. Birklein F, Weber M, Neundorfer B. Increased skin lactate in complex
regional pain syndrome: evidence for tissue hypoxia? Neurology. 2000;55:1213-5.
15. Leis S,WeberM, Isselmann A, SchmelzM, Birklein F. Substance-P-induced
protein extravasation is bilaterally increased in complex regional pain
syndrome. Exp Neurol 2003;183:197-204.
16. Ali Z, Raja S, Wesselmann U, et al. Intradermal injection of norepinephrine
evokes pain in patients with sympathetically maintained pain. Pain
2000;88:161-8.
17. Koban M, Leis S, Schultze-Mosgau S, et al. Tissue hypoxia in complex
regional pain syndrome. Pain 2003;104:149-57.
18. Zollinger P, Tuinebreijer W, Kreis R, et al. Effect of vitamin C on
frequency of reflex sympathetic dystrophy in wrist fractures: a randomised
trial. Lancet 1999;354:2025-8.
19. Perez R, Zuurmond W, Bezemer P, et al. The treatment of complex regional
pain syndrome type I with free radical scavengers: a randomized controlled
study. Pain 2003;102:297-307.
20. Noguchi K et al: Substance P induced by peripheral nerve injury in primary
afferent sensory neurons and its effect on dorsal column nucleus neurons. J
Neurosci. 1995;15:7633.
21. Milan P Stojanovic M. Stimulation Methods for Neuropathic Pain Contro.
Current Pain and Headache Reports 2001, 5:130-137. // MGH Pain Center Department
of Anesthesia and Critical Care, 15 Parkman Street, Massachusetts General
Hospital, Boston, MA, 02114, USA // Current Pain and Headache Reports 2001,
5:130-137.
22. Ochoa J, Verdugo R. Mechanisms of neuropathic pain: nerve, brain, and
psyche: perhaps the dorsal horn but not the sympathetic system. Clin Auton Res
2001;11:335-9.
23. Sicuteri F, Fanciullacci M, Nicolodi M, et al. Substance P theory: a unique
focus on the painful and painless phenomena of cluster headache. Headache
1990;30:69-79.
24. Lynn B. Capsaicin. Actions on nociceptive C-fibers and therapeutic
potential. Pain 1990;41:61-9.
25. DiSabato F, Giacovazzo M, Cristalli G, et al. Effect of hyperbaric oxygen on
the immunoreactivity to substance P in the nasal mucosa of cluster headache
patients. Headache 1996;36:221-3.
26. A. C. Brooks*,1, C. J. Whelan1 and W. M. Purcell2. Reactive oxygen species
generation and histamine release by activated mast cells: modulation by nitric
oxide synthase inhibition. British Journal of Pharmacology 128:585-590 (1999)
27. Fusco BM, Fiore G, Gallo F, et al. "Capsaicin-sensitive" sensory neurons in
cluster headache: pathophysiological aspects and therapeutic indication.
Headache 1994;34:132-7.
28. Ali M. Nature's Preoccupation With Complementarity and Contrariety, The
Principles and Practice of Integrative Medicine Volume II. 2001. Washington,
D.C. Capital University Press (in collaboration with Canary 21 Press, New York).
www.cuim.edu & www.Canary21press.com)
29. Baynes J, Dominiczak MH. Medical Biochemistry. 1999. New York. Mosby.
pp31-39.
30. Pascual J, Peralta G, Sanchez U. Preventive effects of hyperbaric oxygen in
cluster headache. Headache 1995;35:260-1.
31. Mendizabal JE, Umana E, Zweifler RM. Cluster Headache: Horton's Cephalalgia
Revisited. South Med J 1998;91:606-17 [review].
32. Ali M. The Cortical Monkey and Healing. 1991. Bloomfield, New Jersey. Life
Span Books 1991.
33. Ali M. Miracles, and the Bite of the Gray Dog, 1997. Denville, New Jersey,
Life Span Books.
34. Fogan L. Treatment of cluster headache. A double-blind comparison of oxygen
v air inhalation. Arch Neurol 1985;43:362-3.
35. Kudrow L. Response of cluster headache attacks to oxygen inhalation.
Headache 1981;21:1-4.
36. H eterocephalus glaber. www.sciencedaily.com/releases/2003/11/031117073925.htm
37. DiSabato F, Fusco BM, Pelaia P, Giacovazzo M. Hyperbaric oxygen therapy in
cluster headache. Pain 1993;52:243-5.
38 Ali M: Fibromyalgia: an oxidative-dysoxygenative disorder (ODD). J
Integrative Medicine 1999; 3:17-37.
39. Ali M: Darwin, fatigue, and fibromyalgia. J Integrative Medicine
1999;3:5-10.
40. Ali M: ODD trigger points in fibromyalgia: pathogenesis, diagnosis, and
resolution J Integrative Med 1999; 3:38-47.
41. Stanton-Hicks M, Janig W, Hassenbusch S, et al. Reflex sympathetic
dystrophy: changing concepts and taxonomy. Pain. 1995;63:127-33. Also: Drummond
P D. Involvement of the sympathetic nervous system in complex regional pain
syndrome. ijl.sagepub.com/cgi//reprint.
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