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THE PAIN IS IN THE BRAIN

 

INTRODUCTION

Pain is the most common reason for attendance at a doctor in the Western World.  Pain complicates many disorders and interferes with general functioning and quality of life.  All kinds of factors may however, modulate the intensity of pain or its perceived unpleasantness.  Pain however, is not equivalent to functional handicap and there may well be significant genetic factors linking the two.

 

DEFINITION

The International Association for the Study of Pain uses the following definition:  “pain is an unpleasant sensory and emotional experience, associated with actual potential tissue damage or described in terms of such damage”.

 

PAIN WITHIN  HISTORY

Ancient societies thought pain was as a consequence of external magical forces.  Aristotle (384BC – 322BC) theorised that pain was the opposite of “pleasure” and separate from the traditional five senses.  The use of natural electricity for pain management was documented in the 1st century, when headache was treated by the discharge of the organ of electric fishes.

Erasmus Darwin in the 18th Century attributed pain to over stimulation of one of the five senses.  In 1846 it was  demonstrated the difference between touch and pain.  Whereas in the 19th Century Henry Head, showed that pain could be referred to the skin from deep lying structures.  Likewise Head’s studies of Herpes Zoster led to the discovery of the segmental distribution of sensory nerves.

Aristotle believed that the pain was due to evil spirits and Hypocrites thought that it was an imbalance in vital fluids.  In Renaissance Europe it was considered that the pain was perhaps a punishment from God.  It was Descartes in 1644 who recognised that pain messages passed along nerve fibres, until they reached the brain and this transformed the perception from a spiritual mystical experience to a physical common mechanical sensation.

In the late 19th Century there were two theories the “intensive” theory, suggesting that any sensory receptor if stimulated sufficiently would generate pain.  There was also the “specificity” theory whereby there were specific nerve fibres that would generate pain.  We now know that the specificity theory is correct.

 

PAIN IN THE 20TH CENTURY

1964 saw the Melzak-Wall Gate Theory emphasise the mechanisms in the central nervous system, controlling the perception of a noxious stimulus.  Afferent impulses could be modulated downstream from the brain.  Opioid receptors were identified in 1973.  The 21st Century has seen functional MR scanning demonstrating the role of the central nervous system, with the various projections within the brain identified with painful stimuli peripherally.

 

PAIN ANATOMY

Pain signals travel from the periphery to the spinal cord along A-delta or C fibres.  A-delta fibres are thicker than C fibres and their signals are carried significantly faster (5 – 30 metres per second compared to the unmyelinated C fibres 0.5 – 2 m/s).

The pain generated by the A-delta fibres is sharp and is felt first.  This is followed by a duller pain often described as burning carried by the C fibres.

Both the A-delta and C-fibres synapse on second order neurones in the substantia gelatanosa.  The second order fibres then cross the cord via the anterior white commissure and ascend in the spinothalamic tract.  Before reaching the brain, the spinothalamic tract splits into the lateral neospinothalamic tract and the medial paleospinothalamic tract.  The second order neospinothalamic tract neurones carry information from the L-delta fibres and terminate at the ventral post or lateral nucleus of the thalamus where they synapse on 3rd order neurones.  The paleospinothalamic neurones carry information from the C fibres and terminate throughout the brain stem, a tenth of them in the thalamus and the rest in the medulla, pons and periaqueductal grey matter.

It is now known that the thalamic and brain stem terminations, then radiate signal to the insular cortex (distinguishing pain from itch and nausea), the anterior cingulate gyrus (providing the motivational element of pain), the primary and secondary somatosensory cortices, the amygdala (the memory of pain) and also the motor cortex (generating motor functional responses to pain, separate to what is known about the reflex arc).

 

WHY PAIN

It is thought that pain is part of the defence system avoiding harmful situations in the future.  People for instance, with congenital insensitivity to pain have reduced life expectancy.

Different people have different thresholds for pain, which have been measured by psychologists.  People of Mediterranean origin report as painful, some radiant heat intensities that Northern Europeans describe as non-painful.  Italian women were shown to tolerate less intense electric shock than Jewish or Native American women.  People who experience painless heart attacks have been shown to have higher pain thresholds for electric shock, muscle cramp and heat.

 

THE ASSESSMENT OF PAIN

There is no absolute way of validating pain and it is generally regarded, that pain exists at a level of the complaint of the individual.  Analogue pain scales, have been extensively used with 0 being no pain at all and 10 the worst pain imaginable.  There is also for instance the McGill Pain Questionnaire, which allows the individual to indicate which word best describes their pain.  There is a multi-dimensional pain inventory (MPI) which assesses the psychological state of an individual with chronic pain.

 

CLASSIFICATION OF PAIN

There are a range of classifications of pain.  Pain can be defined according to the time that it lasts, such as acute pain or chronic pain. 

Pain can also be classified as follows:-

  1. Nociceptive pain that is pain caused by stimulation of peripheral nerves due to peripheral trauma.  The pain however may also be sub-divided into “visceral”, “deep somatic” and “superficial somatic”.  Or it may be categorised into the mode of stimulation, so that it may be “thermal”, “mechanical” or “chemical”.
  2. Neuropathic pain implies that there is damage to the nervous system and that neuropathic pain can either be peripheral or central.
  3. Pain may also be regarded as phantom as occurs when a limb is lost, psychogenic when it is thought that there are psychological issues compounding the pain.  Melzack  in 1996 however cautioned against the use of the term psychogenic pain, on the basis that we were so ignorant about so many aspects of pain generation.
  4. Other classification schemes also talk about visceral pain as a separate entity.  Pain of a mixed type may be due to cancer or HIV.
  5. Regional pain just refers to pain in a site of the body, such as back ache or abdominal pain.
  6. Some categories will separate headache into a sub-category of primary, secondary to neurological disorders or secondary to systemic diseases and then there are miscellaneous painful conditions, including itching and painful parathesias.  I would also add the condition such as irritable bowel syndrome, chronic fatigue syndrome and fibromyalgia also fall within the concept of chronic, perhaps unexplained pain.

 

CHRONIC PAIN

Chronic pain is usually referred to as intractable pain if it persists for six months or more.  Pain is usually described in terms of stabbing, burning, tearing, squeezing or pulsing.  Acute pain is accompanied by a stress response consisting of an increase in blood pressure, tachycardia, pupillary dilatation and high plasma cortisol levels.  Often there is local muscle contraction contributing, the pain being similar to muscle cramp to give an insight as to the severity.

People with chronic pain experience depression, sleep disturbance, fatigue and decreased mental and physical functioning.  Over 50% of people with chronic pain have depression (personal experience suggests that lowness of mood is almost universal).  The evidence available suggests that depression and chronic pain share common biological pathways namely the serotonergic and noradrenaline systems.

 

THE PATHOPHYSIOLOGY OF CHRONIC PAIN

The consequences of tissue injury, extend beyond the site of injury and generate spinal and super-spinal changes in neuronal excitability as well as neuro chemical changes.  With tissue damage the discharge rate of nerve stimuli increases and inflammatory mediators such as cytokines are released.  The Delta-C and A fibres carry these impulses via the dorsal horn and spinal cord, which then relay the information as described above, to at least six cortical and sub-cortical structures.  It is now known that electrical stimulation of a number of super spinal sites, including the thalamus can produce analgesia.  For instance, the mid brain periaqueductal grey matter when stimulated, generates analgesia and is thought to be a component of the endogenous pain inhibitory system.  The rostral ventral medulla facilitates spinal no susceptive transmissions.  The hyperalgesic response during acute opioid withdrawal, activates the descending pathways from this structure.  Serotonin, noradrenaline and acetylcholine are known to be released during descending inhibitory activation.  Genetic mechanisms are also known to facilitate chronic pain and there are enduring studies hoping to develop new analgesic compounds that targets specific epigenetic protein.

 

CHRONIC PAIN-INDUCED CHANGES IN THE BRAIN

It is now known, that visceral afferent discharges produce changes within the CNS.  The visceral nociceptive stimuli transmit via the dorsal columns.  Visceral pain is relieved after dorsal commissural myelotomy.  Thalamic stimulation can evoke memories of visceral pain.  When noxious stimuli are given to the viscera, it is possible now by PET scanning to show the areas of brain that activates.  Functional neuoimaging also assists in showing that the pre-frontal cortex, anterior cingulate cortex, posterior parietal cortex, thalamus, coudate and amygdala are activated.  Very recent studies show how neuroimaging helps understand the role of cognitive influences on pain and how there can be psychological manipulations to assist people with chronic pain.

Recent studies also show, that chronic pain not only produces functional change, but it actually alters the structure of the brain.

Matt models show that different cortical neuron dendrites are longer with more branches than counterparts in sham-operated animals and their spine density is increased.  Some of these changes will return to normal with resolution of the pain.  All of this provides evidence for the concept that the pain is in the brain and the brain learns the pain.

A similar thinking allows for the explanation of chronic daily headache, irritable bowel syndrome, fibromyalgia and the chronic fatigue syndrome.

 

NEUROCHEMISTRY

Various chemicals generate pain such as substance P which is a neurokinin working within the spinal cord.  It acts principally at what is known as a neurokinin- 1 receptor.  What is surprising however, is that neurokinin-1 receptor antagonists are only partially effective as analgesic agents.  Other pain mediators are glutamate, calcitonin gene-related peptide, bradykinin, histamine, prostaglandins and nitric oxide.  Glutamate for instance plays a major role in the maintenance of hyperalgesia and glutamate receptor antagonists have been shown to be effective analgesic agents.

Opioid receptors are in the dorsal horn and throughout the spinal cord and brain and the clinically used opioids bind to the MU1 opioid receptor.

Activation of various chemical receptors is involved in the development of chronic pain and hence the basis of the development of analgesia.  For instance AMPA or Kainate antagonists will reduce pain.  There are a range of other receptors that are clearly associated with both pain generation and inhibition and all of these are targets for analgesic development which is taking place worldwide.

There is a free radical scavenger known as super oxide dismutase that is an important mediator of pain associated with inflammation.  In animal models an agonist inhibits the hyperalgesic effect with a rapid onset.  It is hoped that the development of drugs that mimic this agent will be effective non-narcotic drugs for the future.

 

The TRANSFORMATION FROM ACUTE TO CHRONIC PAIN

Acute pain may rapidly evolve into chronic pain.  Neuronal expression of new genes can occur within less than half an hour after injury.  Experimental nerve ligation in animals can produce behavioural and histological changes within a day and that again is evidence of the role of the brain in chronic pain.  It is essential that acute pain is treated to stop it progressing to chronic pain.  The plasticity of the nervous system allows for changes to occur once again confirming that the brain learns the pain.  The central neural plasticity results in persistent pain, hyperalgesia, allodynia and the spread of pain to other parts than those involved in the initial pathology.

Different mechanisms are perceived to cause chronic pain to be generated and these include:

  1. An increase in the activity of the pain neuromatrix and its expansion into other cortical areas.
  2. Neuroplasticity
  3. Neurochemical changes in the brain
  4. Structural changes in the brain
  5. Behavioural, histochemical and electro-physiological evidence showing the role of activated astroscytes in promoting chronic pain
  6. Up regulation of genes relevant to pain perception

 

EPIDEMIOLOGY OF CHRONIC PAIN

The prevalence is difficult to determine, because of the differences in definition, but between 10 and 40% of the population will have chronic pain at some time.  The prevalence of chronic pain in severely injured patients three years after the accident has been shown as high as 44%.

 

CENTRAL SENSITISATION
             
Sensitisation is a non associative learning process in which repeated administration of a stimulus results in the progressive amplification of a response.

We now know that sensitisation is characterised by an enhancement of response to a whole class of stimuli in addition to the one that is repeated.  As an example a repeated painful stimulus may make an individual more sensitive to loud noise or a bright light.

My own research unit published on this some years ago demonstrating that migraine sufferers were more sensitive to bright light and loud sound outside of their attacks.

 

EVIDENCE OF CENTRAL SENSITISATION

There is evidence of central sensitisation.

  1. Repeat stimulation of the hippocampus or amygdala in the limbic system will eventually lead to seizures in laboratory animals.  Once this occurs very little stimulation is then required to produce further seizures.  This has led to the thought of “kindling” as part of the mechanism by which epilepsy occurs.
  2. Individuals with temporal lobe epilepsy report negative effects such as anxiety and depression concurrent with limbic dysfunction.
  3. Electrical of chemical stimulation of the right hippocampus causes an increase or strengthening of synaptic signals, a process known as long-term potentiation or LTP.  The LTP of AMPA receptors is thought to be a mechanism underlying memory and learning in the human brain.
  4. There is evidence that neurones in the dorsal horn to the spinal cord become sensitised by peripheral tissue damage or inflammation and it is this mechanism of sensitisation that is thought to sit at the heart of chronic pain.  The changes can be identified with repeated painful stimuli.
  5. Animal research shows that with repeated exposure to painful stimuli the animals’ pain threshold changes and will result in a stronger pain response.  It has been proposed as a mechanism for continued pain after back surgery for instance for a herniated disc causing neural compression.
  6. There is evidence that circumcised newborns have a greater tendency to react more to future injections, vaccinations and other procedures (as measured by an increasing irritability, tachycardia and tachypnea.
  7. Drug sensitisation occurs in drug addiction.  This sensitisation is known to involve changes in brain dopamine transmission, as well as a change in the molecular structure of various neurones.
  8. After peripheral tissue damage, it is known that the spinal dorsal horn neuronal receptive fields continue to expand and the spinal NMDA receptor is important in the induction and maintenance of central sensitisation.

 

THE WORK OF ERIC KANDEL

Eric Kandel looked at the neural basis of sensitisation by observing gill withdrawal of a sea slug, it showed that after habituation from siphon touching (gill withdrawal), applying a paired noxious electrical stimulus to the tail and touch to the siphon led to gill withdrawal.  After the sensitisation, applying a light touch to the siphon without the noxious stimulus produced a strong gill withdrawal response.  This was maintained for several days showing a neuronal learning process.  (In 2000 Eric Kandel was awarded the Nobel Prize).
In simple terms frequent stimulation results in stronger brain memory, so that the brain will respond more rapidly and effectively, when experiencing the same stimulation in the future.  In effect the brain is learning the pain.  Even more so, it would appear that with the resulting change in brain wiring, known as nerve plasticity or central sensitisation, the brain actually “thinks” that it is right to give pain, even for instance when just waking up in the morning and opening the eyes.

 

IMPLICATIONS FOR PAIN MANAGEMENT

With central sensitisation, larger and larger doses of analgesia are required, which in turn seem to enhance the central sensitisation response.  It is thought however, that pre-emptive analgesia or treatment before the pain progresses may reduce that effect.

Recent studies however have shown, that the use of opiates leads to increased central sensitisation and hyperalgesia.

In animal models, morphine doses used to prevent central hyper excitability in a rat model, was at a dose 1/10th that required to abolish activity, after the central sensitisation had developed.

In a human trial of 60 patients undergoing abdominal hysterectomy, those who received 10mg of morphine intravenously at the time of induction  of anaesthesia, required significantly less morphine than post-operative pain control.  Likewise pain sensitivity around the wound (secondary hyperalgesia) was reduced in the morphine pre-treated group.

This has now been shown in a number of other settings such as pre-spinal surgery and with orthopaedic surgery.

A single dose of Paracetamol is known to be morphine sparing in children when given with the induction.  Likewise there is less post-operative nausea and vomiting reported.

An MDA receptor antagonists are also known to be beneficial including Ketamine and Dextromethorphan.  This was used in a trial for people undergoing anti cruciate ligament reconstruction and the amount of post-operative opiate was very much less.
Gabapentin has been used in the same way for patients undergoing mastectomy and hysterectomy and once again reduced the amount of analgesia without side effect.

A similar study has been done with non-steroid anti-inflammatory drugs.

Blocking nerve conduction in the peri-operative period also seems to reduce central sensitisation.  Phantom limb pain is thought to occur as a consequence of kindling of the spinal cord.  A study of 11 patients receiving lumbar epidural blocks with Bupivacaine and Morphine for 72 hours before surgery to stop the development PLS.  The control group saw 5 of the 14 people suffer PLS at six months with 3 continuing at one year.

 

THE TREATMENT OF PAIN

The treatment of central pain remains a great challenge.

In simple terms there are four ways of treating any kind of pain and these are:-

  1. Physical treatments
  2. Injection treatments
  3. Talking therapies
  4. Pharmacotherapy

 
In practical terms physiotherapy input and the use of heat, cold, massage and vibration may be beneficial.

Chiropractic and Osteopathic involvement is often much used by our patients.
There are a range of injection techniques that can be considered including acupuncture and acupressure.  For those with highly resistant pain there may be surgical techniques such as spinal cord stimulation, motor cortex stimulation, deep brain stimulation and even stereotactic thalamotomy.

From the drug perspective, there are first line agents which include the antidepressants, second line agents that include anti-epileptics, Mexiletine and a number of experimental treatments such as intravenous local anaesthetics, Memantine, various cannabis derivatives and capsaicin.

The commonly used first line treatments would be the tricyclic antidepressant drugs.  My own view is that Amitriptyline generates far too may side effects and I have a preference for either Dosulepin or Nortriptyline contrary to the commentary of NICE.

The SSRIs are less effective than the tricyclics, but Venlafaxine and Mirtazapine together with Citalopram may be beneficial.

Various anti-epilepsy drugs have been used included Gabapentin and Pregabalin.  The key is to titrate the dose carefully and they do seem to work very well when in combination with the antidepressants.  Under certain circumstances Carbamazepine, Valproate and Lamotrigine and Levetiracetam have all been used.  Lamotrigine for instance, has been shown in a trial to treat central post stroke pain.  Regrettably, it did not show benefit with a trial of multiple sclerosis related central pain.  Likewise Levetiracetam did not benefit people with post stroke pain.

A whole range of trials have shown that Gabapentin improves quality of life measures in patients.  Pregabalin likewise demonstrated benefit with spinal cord injury up to 600mg daily.  This reduced pain, improved sleep, reduced anxiety and overall patient status.  It was also shown beneficial in central post stroke pain.

Mexiletine a locally active local anaesthetic, has helped post stroke pain and it may be combined with an antidepressant.  ECG examinations however, need to be undertaken and 1/3 of patients will get quite severe nausea and vomiting and hypotension can be another adverse reaction.

Intravenous Lidocaine and intravenous Valproate have also been used with variable success as has Ketamine.

 

CONCLUSION

Acute pain may be generated by peripheral mechanism but once it is chronic this is mediated by the brain. Genetic influences are paramount and will lead to targeted therapies in the future. Overall the management of chronic pain continues to be a major challenge for doctors.  A multi-disciplinary approach, incorporating all of the above treatment options seems to be the best strategy.  Analgesia doesn’t seem to be beneficial for many of these patients and often seems to make the pain worse with sensitisation.

 

 

Dr Michael Gross MA MD FRCP MEWI           
drgross@neurologyclinic.org.uk
www.neurologyclinic.org.uk