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Pain and Neuroscience update, 55th National IAP

Conference Paper · January 2017

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Author: Biswas A, February, 2017, 55th National IAP Conference, Ranchi, India

Abstract:

Keyword Search: Pain, Pain signature, Placebo, fMRI

Introduction: Pain is a complex phenomenon. It’s more a perception than just a sensation (Butler, 2001).
A simple analogy can explain the difference between the sensation and perception. Let’s see the
difference between reading a newspaper and reading a favorite romantic novel. The amount of brain
association with reading the newspaper can be compared with just a sensation, where as the amount of
brain association while reading a favorite romantic novel can be compared with perception. The
difference is probably between the brains association with the event. In case of a sensation the brain is not
strongly adhere to it, just like skimming through the newspaper without any effort to remember it. But
when dealing with perception the brain is little more serious and tries to imagine itself in the event.
Probably the brain is more associated and tries to justify the event in the light of past experiences and
scenarios. The pain is having distributed processing in brain involving multiple structures. Fig 1 explains
the difference of serial processing and distributed processing.

A B C D E B C D E

Fig 1: Serial processing and distributed processing of information

The most widely accepted model of pain is Biopsychosocial model of pain, which is derived from mature
orgasm model first proposed by Gifford L in 1998. In this model pain is seen as a result of biological,
psychological and social interaction. Fig 2 explains the Biopsychosocial model of pain.
 Fig 2: The integration of biological, psychological and social factors

Various types of biological, cognitive, behavioral, & affective factors interact to determine whether a
painful stimulus is inhibited or facilitated. These influences come from periphery as well as brain. Widely
distributed neural network which is genetically predetermined & modified by sensory experience like
injury, pathology, & chronic stress prompt the neuromatrix & lead to activation of perceptual,
homeostatic & behavioral programs, which shapes the meaning of pain. Pain is seen in multiple areas of
the brain such as
• The primary and secondary somatosensory cortex
• Insula
• Anterior cingulate
• Prefrontal cortices thalamus
• Amygdala
• Cerebellum
• Brainstem
• Hypothalamus
• Thalamus
• Limbic structures
• Basal ganglia

Melzack, 2001 proposed the concept of neuromatrix to explain pain association in brain. As per him,
widely distributed neural network that is genetically predetermined & modified by sensory experience
like injury, pathology, & chronic stress prompt the neuromatrix & lead to activation of perceptual,
homeostatic & behavioral programs. The components of the pain system are nociceptors,
neurotransmitters or chemical mediators which again can be of two types. Inhibitory to pain mediators are
norepinephrine, serotonin and facitaltory mediators are bradykinin, serotonin, histamine, prostaglandins,
substance P etc. This leads to secondary changes unrelated to initial tissue damage such as change in
membrane permeability, change in transmission of nerve impulses and sensitization of central and
peripheral nervous system. In CNS there is persistent pain changes activity in the central
nervous system and in the peripheral nervous system there is increased activity of
neurotransmitters/chemical mediators activation of inactive nocioceptors with spontaneous discharge
rates, reduced thresholds & higher discharge rates, changes in characteristics of nerve fibers and
transmission facilitation of noxious stimuli. This change of CNS of PNS based on received sensory input
is called as CNS plasticity (Butler, 2001; Melzack & Wall, 1996).

History of pain treatment and cost of pain: Pain was recognized with different types of it as early as
2000 BC by Egyptians and Mesopotamians. Evidence suggests that they used narcotics such as opium to
treat pain. Hippocrates around 410 BC first recognized pain as a symptom of disease. Then in 1664
French philosopher Rene Descartes proposed pain pathways for the first time, which nearly stood well for
300 years. He also proposed that the pathway from site of origin to spinal cord and then to brain. In 1798,
English chemist Humphry Davy noticed the ease of pain with use of nitrous oxide and pointed that it
could be used for surgical procedure, though it took another 40 years to use gaseous anesthesia for
reversible unconsciousness. The major breakthrough came in 1805, when German pharmacist Friedrich
Serturner isolated morphine, the active ingredient of opium. During the American civil war, a team of
American surgeons identified pain from peripheral nerves, named them as causalgia, nowadays often
called as complex regional pain syndrome. Then in 1899, German company Bayer created Aspirin. In
1906 British neurophysiologist Charles Sherrington proposes the existence of nociceptors, specialized
nerves that detect potentially harmful stimuli, such as extreme temperature. If the intensity is enough to
cause injury, the nerves relay a pain signal to the brain. In 1936, the first pain clinic came up in New York
City’s Bellevue Hospital by Anaesthesiologist Emery Rovenstine. The pain revolution came in 1965, with
the Gate control theory proposed by Psychologist Ronald Melzack and neuroscientist Patrick Wall. By
1973 to 1975 US researchers and British biologists discovered endogenous opioids. PET scan studies
revealed the distributed processing of pain in brain by 1991. It’s now known that people with chronic
back pain are shown to lose as much as 11% of their brain tissue. In 2014, herb Corydalis yanhusuo
having the compound dehydrocorybulbine, was found which binds to dopamine receptors and offers
longer-term relief than opiate drugs. In 2015, researchers find a fundamental difference in how male and
female mice process pain, helping to explain why men and women seem to feel pain differently.

The cost of pain on human mankind is huge. Fig 3, 4 & 5 try to give an idea on cost of pain.

Fig 3: Cost of pain

Fig 5: Growing cost of pain

Recent developments and trends: Chronic pain is the focus of research in pain science. Some
researchers believe that by analyzing the DNA of chronic pain sufferers new horizons can be seen in the
underlying causes and mechanics of chronic pain, which now afflict around one billion people worldwide.
Scientists have now discovered that genetics have a significant role in pain — anywhere from around
20% to 60% of the variability in how people experience pain is attributable to differences in genes,
though nothing has been yet pinpointed any crucial smoking guns in DNA. The first strategy taken by
pain-genetics researchers is to study rare pain disorders that run in families to identify single-gene muta-
tions. It has found that inherited erythromelalgia is caused by a mutation in a gene that causes the sodium-
ion channel NaV1.7 to become overactive. In the second strategy researchers study DNA from large
cohorts of patients is sequenced to try to identify genetic variants and the traits, or phenotypes that
correlate with them. The hope was that such studies would reveal a small number of key pain genes —
those shared by all or many people with various chronic pain disorders. But what researchers found
instead was that pain, like many chronic conditions, is caused by a complex interaction between genes
and the environment influenced by hundreds, if not thousands, of genes in each individual.

Recent fMRI studies have revealed that within the pain matrix of brain there are specific patterns, known
as ‘signature of pain’. Pain-matrix regions are also activated by emotional experiences, such as social
rejection and empathy for, or memory of, pain. Hence it can be argued, that feelings also hurt to some
extent. Another study has found reductions in grey-matter density in the insula and nucleus accumbens in
pain sufferers with the interesting fact that as pain became chronic, activity shifted to brain regions
associated with emotion and reward (Baliki et al, 2012). The extent of this shift was also related to the
strength of the connectivity between the medial prefrontal cortex and the nucleus accumbens (Hashmi et
al, 2013). Therefore it can be said that the main determinant of chronic pain is not the injury, but the
properties of the person’s brain.

A new classification of pain is on the way to develop. German Research Network on Neuropathic Pain
(DFNS) maintaining a large European patient registry with the public–private organization The
Innovative Medicines Initiative (IMI) is enabling a more thorough hunt for such patterns. It contains
about 4,000 patients with their somatosensory profiles, clinical data, quantitative sensory testing (QST)
data, microscopy and skin-biopsy data and, in some cases, genetic data.

Opioids like Morphine are long used as pain killers. They kill pain by targeting µ-opioid receptors on pain
neurons in the spinal cord and brain. By binding to these receptors, opioids inhibit neurotransmitter
release at the junction between pain neurons, blocking the signal. But for the long-term treatment of
chronic pain, the side effects take a toll. As more of the drug enters the body, non-neuronal cells known as
glia take notice. Once thought to be nothing more than a scaffold for neurons, glia are now known to be
active members of the central nervous system. One of the jobs of the glia is to keep watch for foreign
invaders. High opioid doses seem to trigger a defensive response, causing the glia to release immune-
signalling compounds called inflammatory cytokines, which stimulate the sensory neurons that the drugs
are supposed to sooth. The large dose of opioids itself is now causing pain. Researchers have found four
new analogues of endomorphine. Among them the analogue 4 provides much longer duration of analgesia
than morphine. Tolerance is also reduced and the compound does not seem to trigger the release of pain-
stimulating cytokines. In addition, analogue 4 does not seem to be addictive. Several studies have
pinpointed factors that predispose patients to chronic pain. Pre-existing anxiety and depression put people
at risk, as does pre-existing pain. People with chronic migraine are more likely to get chronic knee pain
after a knee operation. Those people have a sensitized nervous system. One of the sensitization
mechanism is called diffuse noxious inhibitory control (DNIC), the DNIC filter the stimulus in spinal
column helping the brain to prioritize its response so that the person pays attention to the stimulus that is
more likely to cause damage in 80% people. But for 20% people it don’t work and therefore they have an
abnormal ability for pain signals to get through to the brain. There are instruments coming up known as
nerve zappers which can specifically stimulate the inhibitory neurons in spinal cord to reduce chronic
pain.

By definition, placebos have no active ingredient, so the idea that someone might benefit from knowingly
taking one — let alone that different placebos could have different effects — seems nonsensical.
Functional magnetic resonance imaging (fMRI) studies were among the first to show that placebos reduce
activity in relevant brain areas when people are subjected to pain. But before the onset of pain, fMRI
scans show something different: receiving a placebo increases activity in the two parts of the brain
involved in emotion and valuation, the prefrontal cortex and the ventral striatum (Wager & Atlas, 2015).
Research is showing that placebo responses can also be learned. This is known as pre conditioning. Pre-
conditioning resulted in a five-fold boost to the average pain relief conferred by a placebo (Schafer et al,
2015). It is also known that preconditioning with different drugs, creates different drug memories and
release of different endogenous substances as pain suppressant. In simple words it means that all placebos
are not same. Researchers have also shown that open placebo can also significantly reduce pain (Amanzio
& Benedetti, 1999; Benedetti F et al, 2016).

PT Implications & Conclusion: The knowledge body of pain science is changing veru rapidly. We the
Physiotherapists must be updated to explore new scopes within our practice to meet the challenges of pain
in a well equipped way. The role of genetics in chronic pain status gives us a bit hope against the dead
lock situation of chronic pain sufferers. Some people are more susceptible to develop chronic pain than
others. A lateral thought then emerges, that there may be people who are more pain resistant than average
population. As pain matrix is activated by emotional experiences, are then emotional peoples are more
susceptible to develop chronic pain. Then is it important to reduce acute pain for first 24 hrs by any
means, and is that should be prioritized for people with emotional nature. Therefore the pain management
should consider individualization based on the meaning, experience of pain of a patient. How in the
management strategy we can include these factors? Can Physiotherapy somehow activate inhibitory
interneuron in spinal cord to reduce pain? Placebos are also showing great influence on pain perception at
brain. Placebo, which was earlier used to be thought as having no ‘real’ effect are showing activation of
different brain areas. Even the placebo effect is reversible and it can be pre conditioned. The question is
like pharmacological placebos are working on brain in Physiotherapy is there a role of placebo? There are
more questions than we ever thought, and more we answer, even more questions are arising.

References:
• Amanzio, M. & Benedetti F, 1999, Neuropharmacological dissection of placebo analgesics:
Expectation activated opioid systems versus conditioning activated specific subsystems, The
Journal of Neuroscience, 19, 01, 484–494.
• Apkarian A V, Sosa Y, Sonty S, Levy R M, Harden R N, Parrish T B & Gitelman D R, 2004,
Journal of Neuroscience, 24, 46, 10410–10415.
• Baliki M N, Bogdan P, Torbey S, Hermann K M, Huang L, Schnitzer T J, Fields H L &
Apkarian V A, 2012, Corticospinal functional connectivity predicts transition to chronic back
pain, Nature Neuroscience, 15, 98, 1117–1119.
• Benedetti F, Frisaldi E, Giudetti L, Pampallona A, Zibetti M, Lanotte M, Lopiano L, 2016,
Teaching neurons to respond to placebos, The Journal of Physiology, 594, 19, 5647 – 5660.
• Brown E, 2016, An incomplete mosaic, Nature, S12, Vol 535
• Butler D S, 2001, The Sensitive nervous system, NOI press, Adelaide.
• Colloca L & Benedetti F, 2006, How prior experience shapes placebo analgesia, Pain 124,
126–133.
• Eisenstein M, 2016, Neuropathy; A name for their pain, Nature, S10, Vol 535.
• Hashmi, J A, Baliki M N, Huang L, Baria A T, Tirbey S, Hermann K M, Schnitzer T J and
Apkarian V A et al, 2013, Brain 136, 2751–2768.
• Inst. Medicine, 2011, Relieving Pain in America, National Academy of Sciences.
• Levine J D, Gordon N C, Fields Howard L, 1978, The mechanism of placebo analgesia, 312,
654–657.
• Melzack R & Wall P D, 1996, The challenge of pain, 2nd ed, Penguin
• Melzack R, Pain and the Neuromatrix in the brain, 2001, Journal of Dental education, 65, 12,
1378-82.
 • Robert E Sorge, Josiane C S Mapplebeck, Sarah Rosen, Simon Beggs, Sarah Taves, Jessica
K Alexander, Loren J Martin, Jean-Sebastien Austin, Susana G Sotocinal, Di Chen, Mu
Yang, Xiang Qun Shi, Hao Huang, Nicolas J Pillon, Philip J Bilan, YuShan Tu, Amira Klip,
Ru-Rong Ji, Ji Zhang, Michael W Salter & Jeffrey S Mogil, 2015, Different immune cells
mediate mechanical pain hypersensitivity in male and female mice, 18, 1081-1083
• Schafer S M, Colloca L & Wager T D, 2015, Journal of Pain 16, 05, 412–420.
• Wager T D & Atlas Y L, 2015, The neuroscience of placebo effects: connecting context,
learning and health, Nature Review Neuroscience, 16, 403–418.
• Wager T D, Atlas L Y, Lindquist MA, Roy M, Woo C W & Kross E, 2013, North England
Journal of Medicine 368, 15, 1388–1397.
• Zadina J E, Nilges M R, Morgenweck J, Zhang X, Hackler L & Fasold M B, 2016,
Endomorphin analog analgesics with reduced abuse liability, respiratory depression, motor
impairment, tolerance and glial activation relative to morphine, Neuropharmacology, 105,
215–227.

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