Melzack and Katz, Pain. Part 7 b: Gate control: "The theory was a leap of faith but it was right!"

The paper, Pain

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

Part 7: Gate control theory has stood the test of time: Patrick David Wall

"The theory was a leap of faith but it was right!" 
-  A. H. Dickenson (2002)

Dickenson adds in his paper (already 11 years old) that Patrick Wall continued to "add to and refine the theory to include changes in afferents, prolonged central excitability, and changes in these systems after nerve damage." 

Here is Dickenson's list of ways the model has expanded since the 60's: 

• Excitations and inhibitions are independently controlled
• Different types of convergent afferent activity may be turned on and off
• There are signs of both short‐ and long‐lasting actions
• More info exists re: transmitters, receptors and channels involved in the transmission, control of noxious input
• New targets and rationales for analgesic therapy including opioids (like this study, on mμ opioid receptor, from June 14, 2013)
• New experimental drugs are available to help in study of transmitters and receptors (same study, on mμ opioid receptor)
• Numerous animal models for clinical pain states, e.g., inflammation, neuropathies
• Several transmitter systems with minor action in acute pain play important roles in persistent pain
• Signalling events are not fixed, are not the same in all situations
• Less destruction of pathways, more emphasis on modulation - reduce excitation or increase inhibition
• Both nociceptive and neuropathic signalling create profound changes in spinal cord and brain - allodynia and hyperalgesia result
• All persisting pains exhibit plasticity
• Peripheral changes drive central adaptations and compensations - numerous sites are involved

Gate control theory has generated thousands of studies. It provided a framework "for examining the interactions between local and distant excitatory and inhibitory systems in the dorsal horn."

Mechanisms subsequently accepted include:

• Inflammation produces peripheral sensitization (Millan MJ 1999)  
• Ectopic activity will occur in damaged peripheral nerves - transmitters will be released continuously into the spinal cord - this will cause subsequent neuronal activity.(Dickenson AH 1995; Suzuki R, Dickenson AH 2000; Millan MJ 1999) 
• Increase in Ca channel activity within the spinal cord drives increased presynaptic transmitter release and postsynaptic neuronal excitability
• N‐type calcium channels, in particular, activate more, contribute to activity evoked by both low‐ and high‐threshold peripheral stimuli
• Upregulation of the α2δ subunit of calcium channels occurs, greater number of channels can become active at any one time
• Gabapentin binds to this component of calcium channels, where it can be presumed to act as an antagonist
• Glutamate and peptides are released by Ca channels into the spinal dorsal horn (Matthews EM, Dickenson AH 2001) - glutamate is the major transmitter in afferent A and C fibres
• Increased glutamate enhances activation of NMDA receptors which can lead to wind-up and central sensitization (Dickenson AH 1995)
• Constant C-fibre activity excites spinal neurons; as they become more excitable their receptive fields increase and secondary hyperalgesia results (McMahon SB, Lewin GR, Wall PD. 1993)
• Glutamate plays pivotal role together with peptides to regulate transmission of nociceptive input; there are 

1. Metabotropic receptors activate biochemical cascades leading to modification of other proteins [e.g., ion channels]
2. AMPA [amino‐3‐hydroxy‐5‐methyl‐4‐isoxazoleproprionic acid] receptors mediate fast synaptic transmission: they set baseline level 
3. NMDA receptors help control synaptic plasticity, memory function, responsible for wind-up which enhances/prolongs trasmission implicating it in many states of central hypersensitivity - only activates when intensity/duration of noxious input exceeds certain level and magnesium blocks are removed (Carpenter KJ, Dickenson AH. 2001). 

SOURCE
AMPA receptor
mediates fast synaptic transmission
[cool gif eh? I doubt they actually spin like this. But at a molecular level, form = function]

• Antagonists can prevent some of the reactions at these sites, e.g., ketamine

.....

This paper is from eleven years ago. I have no idea the extent of the range of discoveries made at the cord level of nociceptive input since then. I know a lot of work has been done on what microglia get up to in there (Beggs S et al 2012), and lately I read a paper on how TRPv receptive C-fibres in the periphery can open the spinal cord/blood barrier for a week or so, allowing larger molecules than usual to bother ascending neurons (Beggs S et al 2010). 

(The above paragraph is my pathetic attempt to touch on just a tiny bit of what's out there to examine. There is a huge amount of research available. Go look at it. Even just some of it. Try to make sense out of whatever you can, about how the nervous system works. We all need to get busy on this if we are to have any hope of getting caught up. We need some kind of collective understanding if we HPSGs are going to have any place in society in the future. Remember, all of us are going to have to know how to deal with pain, in our patients and in ourselves. We're human. )

Gate Control Theory might have been "right".. but as we shall see, it wasn't sufficient. The spinal cord is sort of like that crossover place in a mobius strip where everything changes over to being on the other side all by itself. It's a transition zone. And it's the oldest part of the central nervous system. Fishy ancestors invented spinal cords, and the vertebrate nervous system arrangement in general. But brains came along later, it is thought. Brains select what information to pay attention to. Once they select what they want to attend to they inhibit everything else. See Buzsaki's article about this, Neural Inhibition. Remember what Moseley said about the brain: it's easy to recruit neurons into a neurotag, and very hard to inhibit them later, once they are used to activating. 

Melzack moved pain theory right up past the critter brain, up into the human brain. Which is appropriate, considering that it is humans we deal with, most of the time.. humans who can't fathom how to inhibit pain very well. 

1. Jose Manuel Perez-Aguilar, Jin Xi, Felipe Matsunaga, Xu Cui, Bernard Selling, Jeffery G. Saven, Renyu Liu. A Computationally Designed Water-Soluble Variant of a G-Protein-Coupled Receptor: The Human Mu Opioid Receptor. PLoS ONE, 2013; 8 (6): e66009 DOI:10.1371/journal.pone.0066009

2. Simon Beggs, Tuan Trang & Michael W Salter; P2X4R+ microglia drive neuropathic pain. Nature Neuroscience 15,1068–1073 (2012) doi:10.1038/nn.3155 Published online 26 July 2012

3. Simon Beggs, Xue Jun Liu, Chun Kwan and Michael W Salter; Peripheral nerve injury and TRPV1-expressing primary afferent C-fibers cause opening of the blood-brain barrier. Molecular Pain 2010, 6:74 (open access)

Melzack & Katz, Pain. Part 7: Gate control theory has stood the test of time: Patrick David Wall

The paper, Pain

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale. Part 6h: Gate Control Theory.

GATE CONTROL THEORY

So, last post, we made it to the short section, Gate Control Theory, as a final goodbye to the history of pain.

GATE CONTROL THEORY OF PAIN STANDS THE TEST OF TIME (2002)

A delicious paper listed as reference 12 turns out to be open access!

I want to comb through it, for yummy bits.

Editorial I: Gate Control Theory of pain stands the test of time. Br. J. Anaesth. (2002) 88 (6):755-757, by A. H. Dickenson.

I think this is likely A. H. Dickenson. It looks as though he is a prolific nociception researcher, with 245 papers listed in pubmed. Forty-one of them are open access.

Anyway, here is a bit of what he has to say about gate control theory (2002).

"In 1965, Pat Wall (who died August 8, 2001) and Ron Melzack published their paper in Science, entitled a ‘New Theory of Pain’.1Despite the mention that it was a theory, endless arguments and debates ensued. Poring over the details, arguing over the substrates, all futile and pointless since the theory has stood the test of time and has changed the way we think about pain—the new theory has endured."

 "Why? The theory simply stated, in an elegant and succinct way, that the transmission of pain from the peripheral nerve through the spinal cord was subject to modulation by both intrinsic neurones and controls emanating from the brain (Fig. 1)."  

THE ORIGINAL 1965 PAPER BY MELZACK AND WALL ON GATE CONTROL THEORY!

Reference #1 goes to Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965; 150: 971–9, which [wonderfully!] is open access. 

It's the original!! 

The original paper on Gate Control Theory!! The one that opened a new round in the big battle, helped to force thinking about pain to consider the central nervous system as having some sort of modulatory control over pain perception, helped expand the topic a bit further away from Descartes' ... premise! 

[I foresee that a lot more meandering might have to happen here.]

Source

BACK TO THE 2002 DICKENSON PAPER:

Figure 1 goes to an image depicting gate control theory. 

Source

"Fig 1 The Gate Theory proposed that small (C) fibres activated excitatory systems (black neurone) that excited output cells—these latter cells had their activity controlled by the balance of large‐fibre (A‐beta) mediated inhibitions and were under the control of descending systems."

Ah... yes. 
I can see that we're definitely in for a long meander, for readers of this blog (both of you), and myself. Please pardon me while I reminisce for a little while about Patrick Wall. 
I suppose this is the first (and kind of sad) meander.

Here is a list of his publications. Twenty-one of them are free. 

Patrick David Wall
25 April 1925 – 8 August 2001Source

.................

FURTHER READING ABOUT PATRICK WALL

Patrick David Wall, Wikipedia entry

Eulogy for Patrick D. Wall, Pain Center, by Marshall Devor

Obit in Nature, by Clifford Woolf

Obit NewYorkTimes

Obit in The Guardian

"He once remarked that in order to succeed in science, one has to choose an important subject that no one else is working on, write a book about it and start a journal for it. So he started research on the mechanisms of pain, a subject largely ignored by research at the time, founded Pain, the premier journal of the field, and co-edited the first, and authoritative, Textbook of Pain (1983, fourth edition 1999)."

Patrick Wall's Foreword to Pain: A Textbook for Therapists, Neuroscience and Pain Science for Manual Physical Therapists page on Facebook

Melzack and Katz, Pain. Part 6h: Gate Control Theory

The paper, Pain

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories Part 6g: History of Pain, the cautionary tale.

Continued from last week: Still inside the section titled A BRIEF HISTORY OF PAIN, in Melzack and Katz' paper from 2013, Pain.

.......

From the paper:

"Patients who suffered back pain without presenting signs of organic disease were often labeled as psychologically disturbed and sent to psychiatrists. The concept was simple and often failed to help patients who suffered severe chronic pain. To thoughtful clinical observers,5,6 specificity theory was clearly wrong."

The references listed by the authors are 5. Livingston WK. Pain Mechanisms. New York: Macmillan; 1943, and 6. Livingston WK. Pain and Suffering. Seattle: IASP Press; 1998. Neither of these are online - sorry. No links. In any case I think the implication by Melzack and Katz is that they think Livingston was a thoughtful clinical observer. And that specificity theory was wrong, when it came to pain in the absence of clear pathology. 

In the figure inside the paper, Livingston's reverberatory circuits theory and Goldscheider's summation theory are combined into one diagram, with the comment:

".. in none of these theories was there an explicit role for the brain other than as a passive receiver of messages. Nevertheless, the successive theoretical concepts moved the field in the right direction: into the spinal cord and away from the periphery as the exclusive answer to pain. At least the field of pain was making its way up toward the brain." 

Source

At last we arrive at gate control theory. It has been added to the diagram of the evolution of pain theories as the new (d). 

From Figure 1. in  the 2013 paper, Pain, by Melzack and Katz

Go Melzack. Go Wall.
Next is a short little section about GateControlTheory, so short that I'll include it in its entirety, because very soon, we'll be heading up toward the brain, after taking a sharp upward turn at the dorsal columns, or else crossing the spinal cord and taking a broad swing up at the spinothalamic tract. 

"Theories of pain, like all scientific theories, evolve as result of the accumulation of new facts as well as leaps of the imagination.10 In 1965, Melzack and Wall11 proposed the gate control theory of pain. The final model, depicted in Figure 1(d), is the first theory of pain to incorporate the central control processes of the brain."

Melzack mentions Thomas S. Kuhn in just about every single paper or chapter or book he writes - I think that means he embraced Kuhn's idea of sudden leaps forward in scientific progress.  

To continue:

"The gate control theory of pain11 proposed that the transmission of nerve impulses from afferent fibers to spinal cord transmission (T) cells is modulated by a gating mechanism in the spinal dorsal horn. This gating mechanism is influenced by the relative amount of activity in large- and small-diameter fibers, so that large fibers tend to inhibit transmission (close the gate) while small-fibers tend to facilitate transmission (open the gate). In addition, the spinal gating mechanism is influenced by nerve impulses that descend from the brain. When the output of the spinal T cells exceeds a critical level, it activates the Action System—those neural areas that underlie the complex, sequential patterns of behavior and experience characteristic of pain." 

I remember Moseley saying just a few weeks ago, it's easy to recruit neurons (into neurotags), but it's hard to inhibit them once they've started firing together reinforcing each other. See his clarinet analogy, inside this blogpost.
Since spinal cord is CNS, same goes I should think. 

"The theory's emphasis on the modulation of inputs in the spinal dorsal horns and the dynamic role of the brain in pain processes had a clinical as well as a scientific impact. Psychological factors, which were previously dismissed as ‘reactions to pain’, were now seen to be an integral part of pain processing and new avenues for pain control by psychological therapies were opened. Similarly, cutting nerves and pathways were gradually replaced by a host of methods to modulate the input. Physical therapists and other health-care professionals were brought into the picture, and transcutaneous electrical nerve stimulation became an important modality for the treatment of chronic and acute pain. The current status of pain research and therapy indicates that, despite the addition of a massive amount of detail, the conceptual components of the theory have stood the test of time.12"

Yay! He mentions physical therapists in his paper! 

When it comes to electrical modalities, though, I don't like them. None of them. Never have. They feel so ... electrical. TENS is nice for research but I don't think it's great clinically. Sorry Melzack. I'm way over TENS. Way. 

10   Kuhn TS. The Structure of Scientific Revolutions. Chicago: University of Chicago Press; 1970. 

11   Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965, 150:971–979. 

12   Dickenson AH. Gate control theory of pain stands the test of time. Brit J Anaest 2002, 88:755–757."

Melzack and Katz, Pain. Part 6g, History of Pain continued

The paper, Pain

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain Part 6f: Evaluation of pain theories

At last, we return to the paper itself. [Thank you, both of you who read this blog, for hanging in there while I meandered through Reference 4.]

The section called A BRIEF HISTORY OF PAIN mainly is a cautionary tale, in my opinion, about the danger of basing all your pain research on only anatomical conceptualization.

"This rigid anatomy of pain in the 1950s led to attempts to treat severe chronic pain by a variety of neurosurgical lesions. Descartes’ specificity theory, then, determined the ‘facts’ as they were known up to the middle of the 20th century, and even determined therapy... The psychological experience of pain, therefore, was virtually equated with peripheral injury. In the 1950s, there was no room for psychological contributions to pain, such as attention, past experience, anxiety, depression, and the meaning of the situation. Instead, pain experience was held to be proportional to peripheral injury or pathology."

Therapy. 
Melzack and Katz are talking about medical therapy, of course, but that is what physical therapy has always been attached to - a bio medical model of pain. Only lately has this started to change in any noticeable way. 

"Patients who suffered back pain without presenting signs of organic disease were often labeled as psychologically disturbed and sent to psychiatrists."  

Yeah.
Well, there is still a lot of this going on, depending where you live and work. 

Fortunately, things are turning around. Every so often now, one comes across a paper which emphasizes that non-specific effects of treatment are more useful to patients than any direct effects. I will be reading this one, as soon as I can get my eyes on it: check out the news story from just a couple days ago:  Physiotherapy patient interaction a key ingredient to pain reduction,  research says.  

 Jorge Fuentes holding a spine model in his hands. 

Jorge Fuentes PhD research in Alberta showed; 

"how a physiotherapist interacts with a patient verbally, through eye contact, body language and listening skills is almost as important as the treatment itself."

There were a total of 117 people, all with chronic low back pain,  in four groups:

Group 1: 
5 minutes of PT interaction, limited eye contact, didn't engage the patient, gave them some electrotherapy.

Group 2:
PT stayed with patient the whole 30 minute time, strong communication back and forth, same electrotherapy.

Group 3: 
Same as Group 1, but electrotherapy was not plugged in.

Group 4: 
Same as group 2, but electrotherapy was not plugged in.


Results? Group 2 did best, and group 4 came in second. Electrotherapy is just a ritual - it "works" whether it's plugged in or not, as long as the therapist also is interacting with a patient in a way that supports his or her nervous system's recovery. (Jason Silvernail and I wrote a letter about this, way back when.)

Is anyone surprised? The results (according to the news story, at least) included clinically significant decrease in pain scores and increased pain threshold. I.e., recovery from pain felt in the back likely has nothing much to do with any of the anatomy inside the back - only the nervous system's opinion about its "back", held in some neurotag of the "back" connected to everything else in somebody's life. 

So, it's interesting that in the picture, Fuentes holds a spine model in his hands, reddened disc bulge visible. I don't know why. Maybe he plans to toss it in the trash. Maybe it was a clever idea the photographer had, and nobody protested. See Paul Ingraham's piece on Scary Spine Models.

Models like this are iconic, actually. Sort of like crucifixes in churches. No manual therapy office is complete without one. Even mine.
I would hasten to add, however, that I performed a complete bulge-ectomy on the plastic skeleton that hangs in my office.  I took off every molecule of red disc bulge with fingernail clippers. It's clean now. You'd never know it ever had a disc bulge on it. Much better to remove the disc bulge on the icon - this helps them be removed from patients neurotags a lot easier. 

I remember David Butler, hollering as if way off in the distance, on an online forum, at least a decade ago, 

"We don't treat anatomy - we treat physiology!"

...........................

Please note (both of you) that I will be unable to blog over the weekend about this endlessly riveting paper, as I am busy teaching a workshop in lovely San Jose. I'll be back Tuesday or Wednesday. 

Melzack and Katz, Pain. Part 6f: Evaluation of pain theories

The paper, Pain

Part 1 First two sentences Part 2 Pain is personal Also Pain is Personal addendum., Neurotags! Pain is Personal, Always.

Part 3a Pain is more than sensation: Backdrop Part 3b Pain is not receptor stimulation Part 3c: Pain depends on everything ever experienced by an individual

Part 4: Pain is a multidimensional experience across time

Part 5: Pain and purpose

Part 6a: Descartes and his era; Part 6b: History of pain - what’s in “Ref 4”?; Part 6c: History of pain, Ref 4, cont.. : There is no pain matrix, only a neuromatrix; Part 6d: History of Pain: Final takedown Part 6e: Pattern theories in the history of pain

Evaluation of pain theories
p. 162, Challenge of Pain, Ref. 4 of the paper, Pain.

So, back in 1996, Melzack and Wall looked at this history of pain theories, and asked themselves, how can we make sense out of it? What can we retain? How can we move forward?

"When we consider all the theories examined so far, we see that the 'specific-modality' and 'pattern' concepts of pain, although they appear to be mutually exclusive, both contain  valuable concepts that supplement each other.. when all the theories - from specificity theory onward - are examined together, [it] is apparent that each successive theory makes an important contribution. Each provides an additional mechanism to explain some of the complex clinical syndromes or experimental data that were previously inexplicable. Despite the seemingly small differences, each change contains a major conceptual idea that has had a powerful impact on research and therapy." p. 162-64

Click to make big

Receptor specialization could be accepted without having to toss the idea that information reaching the spinal cord might possibly be repackaged into various patterns. The 'law of adequate stimulus' could be kept, and the idea of some sort of narrow/fixed relationship between receptor and perception could be tossed. In fact, in the time that has elapsed since Von Frey, evidence indicates greater receptor specialization that he could have ever imagined in his wildest dreams. There really isn't any doubt that temporal and spatial patterns provide the basis for sensory perception - this is basic to contemporary neurophysiology and psychology. Goldsheider's ideas about central summation mechanisms has been supported for pathological pain syndromes. Livingston (1943) came up with the idea of spinal reverberatory activity persisting in the absence of noxious input, which seems to still hold some water. Noordenbos idea that large fast fibers inhibit small slow fibre activity still makes sense, "is supported by the evidence that pathological pain is often associated with a loss of large myelinated fibres."

However...

"These theories, nevertheless, fail to comprise a satisfactory general theory of pain. They lack unity, and no single theory has yet been proposed that integrates the diverse theoretical mechanisms." p 164

And furthermore... about that problematic word, "specificity"... Melzack and Wall are determined to be crystal clear:

"The concept of 'specificity' lies at the heart of the controversy that surrounds the evolution of pain theories. It is essential, therefore, that we conclude by examining the concept in order to state unequivocally what we mean by it.

"Throughout this chapter, we have distinguished between physiological specialization and psychological specificity.  

"The former is an indisputable fact. The latter is a theory for which there is no evidence. 

" Neurons in the nervous system are specialized to conduct patterns of nerve impulses that can be recorded and displayed. But no neurons in the somatic projection system are indisputably linked to a single, specific psychological experience."  p 164

And that's still true. My enlargement. The bolds belong to Melzack and Wall.

"Despite our efforts to establish this distinction, (Melzack and Wall, 1962, 1965), many of our colleagues have failed to understand the distinction or continue to use the word 'specificity' in the sense of specialization but without saying so. 

"If we can all agree that 'specificity' means physiological specialization, without implying that specialized neurons must give rise to the experience of pain and only to pain, or that pain can never occur unless they are activated, then we will have eliminated a major source of unnecessary controversy." p. 164

Another way to say this: nociception does not equal pain, and all the textbook that show "pain" receptors/fibres/pathways labelled in their diagrams or text, need to be redone, or else multiple future generations will continue to confuse nociception and pain.

And there will continue to be needless, useless, undermining conflation and confusion.
C'mon people. Tick tock. The pain epidemic continues to grow. And grow. And grow.

Source

............

OK, I realize this has been a very long meander. I promise, next time, back to the paper!