Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_1450_Библиотеки_им_академика_М_И_Перельмана
.pdf
74 D. Shams
which can possibly answer some of the questions surrounding this perception vari-
ability. This chapter briefly reviews pain pathways, discusses genetically inherited
pain disorders, and postulates on future directions of research in regardto the genetics
and treatment of acute pain.
2 Anatomy of Pain Pathways
Nociceptors
In the most basic way, pain is sensed peripherally and transmitted to the brain via the
spinal cord. On a less superficial level, noxious stimuli are detected by a specific set
of peripheral nerve fibers called nociceptors, leading to action potentials which carry
the signal to the spinal cord. It is generally accepted that there are two major classes
of nociceptors, Aδ fibers and C fibers. Aδ fibers are small- to medium-diameter,
myelinated fibers which are important for well-localized, fast pain (or “first pain”).
C fibers, on the other hand, are small-diameter, unmyelinated fibers responsible
for poorly localized slow pain (or “second pain”) [2]. However, if looked at more
closely, even further divisions can be found for both types of fibers. Aδ fibers can
be subdivided into Type I and II Aδ fibers, mediating mechanical/chemical and heat
stimuli, respectively,while C fibers arebelieved to be incredibly heterogenous, as well
as polymodal, being both heat and mechanically sensitive [3]. These nociceptors can
also be differentiated based on which types of receptors and channels are expressed
on their axons and cell bodies. These channels can grant the ability to sense noxious
heat (TRPV1), cold sensation between 10 and 30 °C (TRPM8), acidic environments
(ASICs), and various chemicals (TRPA1) [4].
Ascending Pathways
Noxious signals are transmitted from peripheral nociceptors to the dorsal root ganglia
(DRG) and trigeminal ganglion in the body and face, respectively. From here, primary
afferent nerve fibers synapse upon second-order neurons within the dorsal horn of
the spinal cord, which is itself distinctly stratified into laminae. These second order
neurons then ascend to the brain via the five main ascending pathways, the spinotha-
lamic, spinoreticular, spinomesencephalic, cervicothalamic, and spinohypothalamic
tracts [2].
The spinothalamic tract is the primary pain pathway, arising from lamina I and
V-VII, and finally terminating in the thalamic nuclei; lesions within this tract cause
significant to complete loss of nociception on the contralateral side of the body.
The spinoreticular tract arises from laminae VII and VIII and terminates within the
reticular formation and thalamus; it is thought to be involved in automatic responses
https://t.me/med1917
Genetics of Acute Pain 75
to pain. The spinomesencephalic tract contains axons from laminae I and V which
terminate in a multitude of places, including the mesencephalic reticular formation,
periaqueductal gray,and parabrachial nucleus (which itself projects to the amygdala);
this tract is thought to contribute to the emotional aspect of pain and be involved in
descending modulatory pathways. The cervicothalamic tract has a function similar
to the spinothalamic tract but contains axons from laminae III and IV. Finally, the
spinohypothalamic tract contains axons from laminae I, V, and VIII which then
synapse to the hypothalamic nuclei; this regulates the endocrine and cardiovascular
responses to pain [2, 4]. The signal is then carried to the cortical structures, such as
the prefrontal cortex, the somatosensory cortex, the anterior cingulate gyrus, and the
insular cortex, none of which are in and of themselves essential to pain regulation,
but all of which are critical components in the perception and response to painful
stimuli.
3 Heritability of Pain
When discussing heritability within the human population, twin studies are one of
the classic tools implemented to determine what role, if any, genetics play in a partic-
ular phenotype. Typically, pairs of monozygotic (MZ) and dizygotic (DZ) twins are
compared, assuming that environmental influences will be similar across the popula-
tion. If the concordance between MZ is greater than the DZ concordance, heritability
can then be calculated. However, pain is such a broad phenotype with the possibility
of multifactorial traits, that other forms of study may also be important. These include
family analyses and genetic association studies to evaluate single nucleotide poly-
morphisms (SNPs) [5]. Additionally, a distinction needs to be made from genetic
contributions to pain conditions and experimental pain responses. Below, we will
break down the heritability of pain conditions themselves as well as the heritability
of enhanced sensitivity to pain.
Twin Studies
Numerous pain phenotypes have been evaluatedwith twin studies to hunt for evidence
of heritability. As noted above, given the differences present in pain phenotypes, this
is not always an easy task; however, the genetic heritability has been indicated in
several pain phenotypes.
https://t.me/med1917
76 D. Shams
Headaches
One of the most studied of these phenotypes is headaches, including migraines,
tension, recurrent, and temporomandibular joint disorders (TMD). Twin studies
looking at heritability in migraines have demonstrated a consistent, though wide,
range, estimating the heritability to range anywhere from 33–77% [6]. The largest
study, which included data from almost 30,000 pairs across eight countries, found
the overall heritability to be 46%, or nearly half [7]; this value is corroborated by
multiple additional studies. Tension-type headaches have also been found to demon-
strate heritability of almost 50%, with the largest study reporting heritability of 48%
for men and 44% for women [8].
Back and Neck Pain
In addition to headaches, back and neck pain, particularly low back pain, has been
the subject of multiple twin studies. This has proved to be difficult given a large
discrepancy in the definition of low back pain, but a meta-analysis of these studied
found an overall heritability of just over one-third, or 34% [6]. The heritability of
neck pain was found to be similar, although, once again, significant heterogeneity
existed within the data sets, making a meta-analysis difficult.
Other Pain Modalities
In addition to headaches and back/neck pain, twin studies have been conducted for
other pain phenotypes, with significant heritability found in some, but not in others
(usually due to inadequate data). These include irritable bowel syndrome (IBS),
found to have heritability of around 25%, rheumatoid arthritis, with heritability of
nearly 50%, and chronic widespread pain (CWP), also with heritability around 50%.
Studies evaluating osteoarthritis contained small sample data, making it difficult to
reach any sort of conclusion regarding heritability; this remained true for carpal
tunnel syndrome, ankylosing spondylitis, psoriatic arthritis, and gout [5, 6].
Experimental Pain Phenotypes
Experimental pain studies have attempted to unlock how pain is processed indepen-
dent of the disease processes themselves. These pain sensitivity studies have sought
to increase physiologic understanding through measuring responses to cold and heat
pain. Just as with twin studies examining heritability for known pathologies, twin
https://t.me/med1917
Genetics of Acute Pain 77
studies looking at experimental phenotypes also contained significant variability;
they do, however, suggest there is heritability for experimental pain responses, likely
more for cold-pressor pain (~50% heritability) than for heat pain measures (~25%
heritability). Additional studies have also demonstrated correlations between pain
tolerance and sex, ethnicity, and psychological traits (i.e. fear of pain, pain catastro-
phization). It has been established repeatedly that women have lower pain tolerance
than men [9, 10], however, women are more likely to have their pain under-treated
post-operatively and instead receive sedatives rather than analgesics compared to
men [11]. Asians have also been shown to suffer from greater experimental pain
perception compared to non-Hispanic Whitess [9, 12].
Psychological traits have also exhibited a correlation with experimental and expe-
riential pain, just as they are risk factors for developing chronic pain post-operative
pain. In a study by Patanwala et al., the Pain Catastrophizing Scale (PCS) and Fear
of Pain Questionnaire-III (FPQ-III) were both revealed to correlate well with pain
tolerance in cold water tests; those who were higher on the catastrophizer or fear of
pain scales were much quicker to remove their hands from cold water baths than their
counterparts who scored lower [9]. Unfortunately, there is lack of studies examining
the relationship between experimental pain and clinical pain phenotypes. Further
study into this could lead to a finetuning of experimental models looking at pain
processes in the future [5, 13].
4 Candidate Genes
Multiple studies have explored the connection between genetics and pain, both for
specific pain conditions as well as for experimental pain responses. Many of these are
related to chronic pain conditions, such as temporomandibular disorders (TMD) or
those mentioned above within the twin studies, but others have looked at the presence
of SNPs in experimentally induced pain. See Table 1 for a brief overview.
Ion Channels
Ion channels vary in their molecular structure but are all membrane proteins which
help to transport ions into or out of the cell. Broadly speaking, they are separated
into voltage-gated and ligand-gated channels. Of the more than 400 channel genes
encoded within the human genome and the ten known subtypes of voltage-gated
sodium channels, Na
v
1.7, 1.8, and 1.9 are expressed almost exclusively within noci-
ceptive neurons [14]. One of these, the Na
v
1.7, has been found to be associated with
the ability to sense pain and is encoded by the SCN9A gene; a loss-of-function muta-
tion within this gene causes familial insensitivity to pain. This, of course, may lead
to significant complications, such as accidental trauma, burns, or skin ulcers. Studies
also show that lesions within this gene may decrease post-operative pain sensitivity.
https://t.me/med1917
78 D. Shams
Table 1 Genes, their respective proteins, and their role in human pain
Encoding
gene
Protein Function Phenotype
SCN9A Na
v
1.7 sodium channel Voltage-gated
sodium channel
Increased risk of
sciatica, OA,
post-lumbar
discectomy, and
phantom limb pain [24]
CACNA1A Ca
v
2.1 calcium channel Voltage-gated
calcium channel
Increased risk of
neuropathic pain after
mastectomy [25]
COMT Catecholamine-O-methyltransferase Catecholamine
degradation
Higher enzyme activity
leads to increased
sensitivitytopain[17]
GCH1 GTP cyclohydrolase 1 BH
4
synthesis Decreased sensitivity to
experimental pain [18]
OPRM1 Mu-opioid receptor Opioid signaling Decreased analgesic
response to morphine
[19]
MC1R Melanocortin-1 receptor Controls type of
melanin being
produced
Red hair, fair skin,
increased pain
sensitivity and opioid
requirements [21]
CYP2D6 Cytochrome P450, family 2,
subfamily D, polypeptide 6
Drug metabolism Gene duplication results
in increased sensitivity
to codeine [23]
On the contralateral side of this, a gain-of-function mutation within this same gene
may lead to primary erythromelalgia, characterized by burningpain in the extremities,
or paroxysmal extreme pain disorder (PEPD), characterized by mandibular, ocular,
and rectal pain. Studies have shown a correlation between this gene and increased
risk of sciatica, osteoarthritis (OA), pancreatitis, and post-lumbar discectomy pain
[15].
Similar gain-of-function and loss-of-function mutations have been found in other
ion channels, leading to variations of familial hemiplegic migraines (FHM). These
mutations have been identified within Ca
v
2.1 calcium channels, Na–K ATPase, and
the Na
v
1.1 sodium channel [4]. Even potassium channels have been recognized in
pain pathologies. The voltage-gated potassium channel, K
v
9.1, has a variant which
leads to greater pain and decreased post-operative pain improvement in patients
undergoing lumbar discectomy and amputees with phantom limb pain or neuropathic
pain.
https://t.me/med1917
Genetics of Acute Pain 79
Catecholamine-O-Methyltransferase (COMT)
The COMT gene is one of the better studied SNPs in the field of pain genetics.
The met158val SNP has been identified as a contributor in the observed differences
in human responses to pain. The COMT gene encodes a protein that is involved
in catecholamine degradation; the val
158
met SNP results in higher enzyme activity
which then leads to an increased sensitivity to pain, leading to an increased morphine
requirement in cancer patients [16]. A 3-year prospective trial identified 3 main
haplotypes (low, average, and high pain sensitive) of the COMT gene based on
responses to experimental pain. They then found that having even one low pain
sensitive haplotype reduces the risk of developing TMD [17].
Guanosine Triphosphate (GTP) Cyclohydrolase 1 (GCH1)
GCH1 is the catalyst in the rate limiting step of the conversion of GTP to tetrahy-
drobiopterin (BH
4
). BH
4
is involved the production of nitric oxide and citrulline,
eventually leading to the production of serotonin and breakdown of phenylalanine to
tyrosine [16]. It was initially found to be involved in neuropathic and inflammatory
pain in animal research; further human research helped to identify variants which led
to a decrease in the risk of developing chronic pain and a reduction in experimental
pain sensitivity [18].
OPRM1 Gene
The opioid mu-receptor is encoded by the OPRM1 gene. This gene has multiple
variants, though the 118 A > G is the most extensively studied and has been found
to be associated with human responses to analgesia and pain. Patients with this SNP
have been found to have a decreased response to morphine, both in pain relief and
pupillary miosis. While the full reason for this effect is unknown, it is believed that
this SNP leads to decreased effects of opioids in the areas of the brain most strongly
associated with processing pain intensity [15, 19].
Melanocortin Receptor (MC1R)
It has been a long-standing saying that those with red-hair and fair skin require more
anesthesia to remain sedated and greater analgesia to remain comfortable following
surgery. While this was not initially accepted within the medical community itself,
multiple SNPs in the MC1R gene have now been identified which demonstrate the
https://t.me/med1917
80 D. Shams
phenotype of fair skin, red-hair, and increased pain sensitivity. It is postulated that
MC1R is expressed in glial cells and the periaqueductal gray as well, thereby leading
to this correlation [20, 21]. Thus, individuals with these SNPs require high doses of
pain medication compared to those without. Interestingly, however, female carriers
of these variants show greater analgesic effects to k-opioid analgesics where male
carriers do not, demonstrating an additional sex-specific response within the k-opioid
system [22, 23].
Cytochrome P450 2D6 (CYP2D6)
The P450 system is involved in the metabolism of many medications. The 2D6
polypeptide catalyzes codeine to morphine, a metabolic conversion necessary to
illicit the clinical effects desired from analgesic administration. On its own, codeine
has a 200 times lower affinity at the mu-opioid receptors than morphine; therefore,
it depends strongly on this conversion for its clinical effects. Duplications of this
gene thus lead to faster metabolism of codeine to morphine, thus increasing its effec-
tiveness. The opposite is true for “poor metabolizers” lacking a functional CYP2D6
gene, whereby codeine will have minimal to no analgesic effect. These genetic vari-
ants are also relatively common; gene multiplications are found among nearly 3% of
Caucasians and nonfunctional genes are found among 7% of Caucasians [23]. This
means that nearly 10% of the Caucasian population gets no pain relief from codeine,
as opposed to 0.5% of the African-American or Asian populations.
5 Future Directions
The future of genetics and its role in pain perception and management remains
wide open for additional research and breakthroughs. As the rapid production of the
COVID-19 vaccine has shown us, new techniques are constantly being developed
which can be applied to the realm of pain and, more specifically,acute pain. This being
said, additional studies are needed to account for the variability seen in the human
population regarding pain phenotypes and pain reporting. As our understanding of
how genetic constitution impacts perioperative analgesia improves, we will ideally
begin to leverage this enhanced insight to create truly patient centered treatments,
currently seen only in science fiction. Using genotypic information as a guide to
analgesic therapy could be in the near future; for instance, nerve growth factor, NGF
(a topic not covered in this chapter), has been identified as a target after a SNP
from a single family demonstrated a hereditary insensitivity to pain. This led to the
production of an NGF-inhibiting antibody called tanezumab, which can function as
an analgesic for OA pain [26]. In this same vein, it is possible that a blockade of
GCH1 may lead to the prevention of cancer pain or that selective Na
v
1.7 inhibitors
https://t.me/med1917
Genetics of Acute Pain 81
may reduce pain sensitivity [16]. Additionally, with the continued rise of artificial
intelligence (AI), the research may advance at an even quicker clip.
Key Points
1. Pain perception is a delicate and complicated procedure and variations at any
step of the signaling pathway, from the nociceptors to the cortical structures,
may lead to increased or decreased pain sensitivities.
2. Identification of various genes via animal research can be combined with cohort
analyses of humans to pinpoint bottlenecks and targets for future, genetically
driven treatments.
3. Rapid advancement of research in this field will lead to further targets for
analgesics and, hopefully, the analgesics themselves.
References
1. Gan TJ, Habib AS, Miller TE, White W, Apfelbaum JL. Incidence, patient satisfaction, and
perceptions of post-surgical pain: results from a US national survey. Curr Med Res Opin.
2014;30:149–60.
2. Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA, Hudspeth AJ, eds. 24: Pain. In: Principles
of neural science, Fifth Edition., 2000.
3. Basbaum AI, Bautista DM, Scherrer G, Julius D. Cellular and molecular mechanisms of pain.
Cell. 2009;139:267–84.
4. Renthal W. Pain genetics. In: Rosenberg’s molecular and genetic basis of neurological and
psychiatric disease, 2015:1089–100.
5. Fillingim R, Wallace M, Herbstman D, Ribeiro-Dasilva M, Staud R. Genetic contributions to
pain: a review of findings in humans. Oral Dis. 2008;14:673–82.
6. Nielsen C, Knudsen G, Steingrímsdóttir Ó. Twin studies of pain. Clin Genet. 2012;82:331–40.
7. Mulder EJ, van Baal C, Gaist D, Kallela M, Kaprio J, Svensson DA, Nyholt DR, Martin NG,
MacGregor AJ, Cherkas LF, Boomsma DI, Palotie A. Genetic and environmental influences
on migraine: a twin study across six countries. Twin Res. 2003;6:422–31.
8. Russell MB, Levi N, Kaprio J. Genetics of tension-type headache: A population based twin
study. Am J Med Genet Part B Neuropsychiatric Genet. 2007;144B:982–6.
9. Patanwala AE, Norwood C, Steiner H, Morrison D, Li M, Walsh K, Martinez M, Baker SE,
Snyder EM, Karnes JH. Psychological and genetic predictors of pain tolerance. Clin Transl
Sci. 2019;12:189–95.
10. Pieretti S, Giannuario AD, Giovannandrea RD, Marzoli F, Piccaro G, Minosi P, Aloisi AM.
Gender differences in pain and its relief. Ann dell’Ist Super di sanita. 2016;52:184–9.
11. Calderone KL. The influence of gender on the frequency of pain and sedative medication
administered to postoperative patients. Sex Roles. 1990;23:713–25.
12. Cong X, Tan Z, Weidig T. Sex, Race, and Genomics of Pain. In: Dorsey SG, Starkweather AR,
editors. Genomics of pain and co-morbid symptoms., 2020:181–91.
13. Angst MS, Phillips NG, Drover DR, Tingle M, Ray A, Swan GE, Lazzeroni LC, Clark JD. Pain
sensitivity and opioid analgesia: a pharmacogenomic twin study. Pain. 2012;153:1397–409.
14. VenterJC, Adams MD, Myers EW,Li PW, Mural RJ, Sutton GG, Smith HO, YandellM, Evans
CA, Holt RA, Gocayne JD, Amanatides P, Ballew RM, Huson DH, Wortman JR, Zhang Q,
Kodira CD, Zheng XH, Chen L, Skupski M, Subramanian G, Thomas PD, Zhang J, Miklos
GLG, Nelson C, Broder S, Clark AG, Nadeau J, McKusick VA, Zinder N, et al. The Sequence
of the human genome. Sci. 2001;291:1304–51.
https://t.me/med1917
82 D. Shams
15. James S. Human pain and genetics: some basics. Br J Pain. 2013;7:171–8.
16. Lötsch J. Genetic variability of pain perception and treatment—clinical pharmacological
implications. Eur J Clin Pharmacol. 2011;67:541–51.
17. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigurdsson A, Belfer I, Goldman D, Xu
K, Shabalina SA, Shagin D, Max MB, Makarov SS, Maixner W. Genetic basis for individual
variations in pain perception and the development of a chronic pain condition. Hum Mol Genet.
2005;14:135–43.
18. Tegeder I, Costigan M, Griffin RS, Abele A, Belfer I, Schmidt H, Ehnert C, Nejim J, Marian
C, Scholz J, Wu T, Allchorne A, Diatchenko L, Binshtok AM, Goldman D, Adolph J, Sama
S, Atlas SJ, Carlezon WA, Parsegian A, Lötsch J, Fillingim RB, Maixner W, Geisslinger G,
Max MB, Woolf CJ. GTP cyclohydrolase and tetrahydrobiopterin regulate pain sensitivity and
persistence. Nat Med. 2006;12:1269–77.
19. Reyes-Gibby CC, Shete S, Rakvåg T, Bhat SV, Skorpen F, Bruera E, Kaasa S, Klepstad P.
Exploring joint effects of genes and the clinical efficacy of morphine for cancer pain: OPRM1
and COMT gene. Pain. 2007;130:25–30.
20. Kwon AH, Flood P. Genetics and gender in acute pain and perioperative opioid analgesia.
Anesthesiol Clin. 2020;38:341–55.
21. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KVS, Lariviere WR, Groce MK,
Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby
VJ, Grisel JE, Fillingim RB. The melanocortin-1 receptor gene mediates female-specific
mechanisms of analgesia in mice and humans. Proc National Acad Sci. 2003;100:4867–72.
22. Edwards RR. Genetic predictors of acute and chronic pain. Curr Rheumatol Rep. 2006;8:411–7.
23. Lötsch J, Geisslinger G. Current evidencefor a genetic modulation of the response to analgesics.
Pain. 2006;121:1–5.
24. Reimann F, Cox JJ, Belfer I, Diatchenko L, Zaykin DV, McHale DP, Drenth JPH, Dai F,
Wheeler J, Sanders F, Wood L, Wu T-X, Karppinen J, Nikolajsen L, Männikkö M, Max MB,
Kiselycznyk C, Poddar M, te Morsche RHM, Smith S, Gibson D, Kelempisioti A, Maixner W,
Gribble FM, Woods CG. Pain perception is altered by a nucleotide polymorphism in SCN9A.
Proc National Acad Sci. 2010;107:5148–53.
25. Habib AS, Kertai MD, Cooter M, Greenup RA, Hwang S. Risk factors for severe acute pain
and persistent pain after surgery for breast cancer: a prospective observational study. Reg
Anesthesia Pain Med. 2019;44:192.
26. LN E, ST J, BC A, Masoud M, SD L, SM D, BM T. Tanezumab for the treatment of pain from
osteoarthritis of the knee. New Engl J Med. 2010;363:1521–31.
https://t.me/med1917
Pain Management Consent
Considerations
Elizabeth Wilson and Kristopher Schroeder
Abstract Healthcare professionals must consider patients as collaborators in the
process of healthcare decision making. In matters of perioperative pain management,
it is important to consider and include patients in decisions that may be impacted by
their personal history of pain management/analgesic administration, value system/
thought process regarding pain management, and the relative impact of potential
complications related to analgesic procedures and opioid analgesics. To make these
decisions, healthcare professionals must consider the ability of patients to make
decisions in the setting of pain and polypharmacy and if the use of adjunct/surrogate
decision makers may be appropriate/beneficial. In addition, it is important to consider
how information is conveyed and the degree of detail that is required to ensure that
patients are equipped to make a decision that best aligns with their belief system and
values. Finally, patient decisions must be respected, and they must know that they
possess the autonomy to be ultimately responsible for the decisions that will impact
their healthcare delivery.
Keywords Consent
· Capacity · Competency · Surrogate · Disclosure
1 Introduction
Healthcare professionals are required to obtain consent prior to performing proce-
dures and administering medications. However, this practice has evolved greatly
over time and continues to do so as patients desire more involvement in their health-
care decision making process. In many cases, healthcare professionals may struggle
with the best course of action regarding what to disclose, what not to disclose, to
E. Wilson · K. Schroeder (
B
)
Department of Anesthesiology, University of Wisconsin School of Medicine and Public Health,
Madison, WI, USA
e-mail: Kmschro1@wisc.edu
E. Wilson
e-mail: Elizabeth.wilson@wisc.edu
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2024
A. Abd-Elsayed and K. Schroeder (eds.), Perioperative Pain Management,
https://doi.org/10.1007/978-3-031-67648-2_6
83
https://t.me/med1917
Соседние файлы в папке Библиотека им академика М.И. Перельмана