PAIN: OF COURSE IT’S ALL IN YOUR HEAD

NEUROBIOLOGY OF PAIN

DEFINITION

IASP: "Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage". Even the authors were aware of this definition’s inadequacy, and hastened to add: "Pain is always subjective… This definition avoids tying pain to the stimulus".

Despite the disclaimer, this definition DOES tie the sensation to the stimulus, perpetuating the centuries old fallacy. It does not, and cannot, explain many of the perplexing aspects of pain experience, and it does not consider the crucial influence of the brain on the sensation and the perception of pain.

  1. The brain can generate pain, create a perceptual experience, independent of the peripheral input, i.e., regardless of the presence or the extent of tissue damage or pathology.
  2. The brain is continually modified by experience and sensory input.

THE PUZZLE OF PAIN

Without the contributions of modern neuroscience, it is impossible to unravel the multitude of the pain puzzles:

  1. Well known instances of NO PAIN with major injuries
  2. Excruciating PAIN in missing structures (phantom pains), or denervated structures (below spinal cord section in paraplegics)
  3. PAIN persisting, after complete healing of injury
  4. PAIN provoked by touch, or no stimulus at all
  5. PAIN that is delayed, or non-anatomically spread

NOCICEPTION AND PAIN PATHWAYS

Stimuli from the periphery (mechanical, chemical, thermal) are transmitted to the spinal cord through the sensory afferent nerves.

Damaged tissue is a source of many amines and peptides that stimulate sensory nerve endings: bradykinin, adrenaline, 5HT, PGE2, IL-1, IL-6, TNF-alpha, etc.

These afferents synapse on the dorsal horn second order neurons in the spinal column (projection neurons), which form pathways extending to the brain – primarily thalamus and somato-sensory cortex.

Acute, physiological pain is mediated in the spinal synapses mainly by the GLUTAMATE-activated AMPA type of glutamate receptors.

In addition to glutamate, excitatory transmitters include AcCh, substance P, and CGRP, while GABA, enkephalin, 5HT and NA provide the inhibitory neurotransmission.

NEUROBIOLOGY OF CHRONIC PAIN

Chronic pain is not just a prolonged acute pain; it is a distinct entity, with many functional and structural alterations of the peripheral and central nervous system.

ERIPHERAL SENSITIZATION – PRIMARY HYPERALGESIA

Peripheral nociceptive hyperexcitability is induced through increased receptor (autosensitization) or cell membrane (heterosensitization) reactivity to stimuli, usually sustained presence of inflammatory factors.

CENTRAL SENSITIZATION – SECONDARY HYPERALGESIA

Central hyperexcitability is the key process in the generation of chronic pain. It is mediated by NMDA-type of post-synaptic glutamate receptors, and it results in transcriptional changes and manufacturing of the c-fos protein (the marker of central sensitization) in the second order dorsal horn projection neurons.

Repetitious and intense activation of the high-threshold C-fibers and AMPA post-synaptic receptors results in activation of the NMDA post-synaptic receptors (through dislodging the Mg ions and opening the N and Ca channels to Ca influx) and the NMDA mediated WIND-UP phenomenon (augmented response of the dorsal horn neurons to the same intensity stimuli).

Activation of the NMDA-receptors represents the first step in central sensitization, i.e., the transition from acute to chronic pain.

Knowing this makes it easy to realize that adequate treatment of physiological, nociceptive pain is the most important goal of acute pain management – prevention of central sensitization!

Other changes involved in central sensitization include substance P – NO (nitric oxide) cascade (with expansion of the receptive fields), increased release of NPY, VIP, galanin, and somatostatin from the pre-synaptic C-fiber terminals, hyper-sensitization of the WDR (wide dynamic range) neurons to non-nociceptive stimuli, expression of substance P by A-fiber pre-synaptic terminals, and sprouting of A-fiber terminals into the superficial layers of the dorsal horn (thus synapsing onto the nociceptive second order neurons).

Reorganization or remodelling of the synapses at the dorsal horn level, as well as at the brainstem, thalamus, and somatosensory cortex levels, is a well-documented phenomenon, referred to as neuronal plasticity, responsible for a variety of chronic pain syndromes.

Central sensitization and neuroplastic remodeling are responsible for all the main features of chronic pain: hypersensitivity to nociceptive stimuli (hyperalgesia), perception of pain upon non-nociceptive stimulation (NNP and allodynia), expansion of the pain-receptive fields and trigger-zones, and delayed pain.

Changes in central sensitization can be viewed as:

  1. FUNCTIONAL (NEUROCHEMICAL) HYPEREXCITABILITY:

    Activation of the NMDA- receptors, wind-up, sensitization of WDR neurons, expression of substance P by A-fibers

  2. STRUCTURAL (NEUROANATOMICAL) HYPEREXCITABILITY:

Dying-off of C-fiber terminals, sprouting of A-fiber terminals, extensive reorganization of the somatosensory cortical maps, remodeling in the brainstem, cerebellum, basal ganglia, and motor cortical areas.

DYSFUNCTIONAL DESCENDING INHIBITION – FAILURE OF INTERNAL ANTINOCICEPTION

As illustrated in PAIN PATHWAYS, nociception activates not only the afferent pathways, but also a variety of segmental and descending, inhibitory or anti-nociceptive pathways (SLIDE 5). Increased brainstem CCK, and deficiencies in the descending enkephalin, 5HT, and NA pathways, can all contribute to dysfunctional anti-nociception.

Processing of pain at the brain level has profound implications for both, the perception of pain, and for the management of pain.

Ascending pain pathways are relayed through the thalamus to the somatosensory cortex, which is responsible for the initial localization and the intensity of the stimulus (SENSORY-DISCRIMINATIVE function), as well as to the limbic brain structures, esp. the anterior cingulated cortex, which is responsible for the unpleasant, aversive aspect of the experience (AFFECTIVE-MOTIVATIONAL function). Both of these areas communicate extensively and reciprocally with the prefrontal cortex, which brings the situational and memory context to the experience (COGNITIVE-EVALUATIVE function).

These three aspects of pain experience (R. Melzack’s gate and neuromatrix theory of pain) make a variety of pain treatment modalities potentially helpful, and at the same time provide the neurophysiological and neurostructural explanation of these modalities’ efficacy (dismissing, in the process, all kinds of hogwash that has been written about "psychogenesis" of pain).

 

CHRONIC PAIN SYNDROMES

Chronic pain is generally categorized, according to etiological factors, as stemming from tissue damageinflammatory pain, or from

nerve damageneuropathic pain. The former is evident in various injuries (low back pain), infections, inflammatory diseases (RA, IBD, SLE) and immune/neuroendocrine dysfunctions (possibly FM/CFS, MPS). The latter is encountered in diabetes, certain infections (shingles), cancer, traumatic nerve injury, and following amputations (limb, breast).

Opioids are exceedingly effective in managing inflammatory pain, whereas they are less effective in managing neuropathic pain, due to the loss of pre-synaptic opioid receptors, and the extensive re-wiring of the dorsal horn synaptic circuits.

Low back pain

In up to 85% of sufferers, there is no detectable damage ("no objectively demonstrable organic pathology"); in only about 15% can one of the five recognizable causes (herniated disc, arthritis, infection, tumor or fracture) be demonstrated.

In addition, it is estimated that about 10% of low back pains develop a neuropathic dimension, making the picture even more puzzling. The vast majority of chronic low back pain sufferers continue to be under-treated or maltreated, labeled as "somatizers" or malingerers, despite ample evidence for central sensitization and somatosensory mapping reorganization in such patients.

Fibromyalgia and Myofascial Pain Syndrome

There is ample evidence in these disorders, as well, of altered central processing of the incoming nociceptive and non-nociceptive stimuli, at both the spinal and the brain level. Incoming stimuli from muscle C-fiber afferents are much more potent inducers of central sensitization than skin afferents, explaining lower pain threshold (hyperalgesia) and pain on movement (proprioceptive allodynia) in these patients. In addition, a dysregulated neuroendocrine stress response (decreased cortisol, growth hormone and IGF-1 secretion) may compound the picture in about a third of patients.

Phantom limb pain

Phantom pains affect over 70% of amputees, and persist for 2-7 years in about 60% of them; fewer than 15% obtain total pain relief. Extensive somatosensory cortex reorganization, with expansion of the trigger zones, has been demonstrated in numerous brain imaging studies.

Peripheral ectopic discharges (from the stump neuroma), deafferentation hyperexcitability, and unmasking of the underlying silent connections, may all be contributory.

In addition to phantom limb pain, phantom pains following mastectomy, and phantom body pains below the spinal cord section in paraplegics, are gaining increasing recognition.

DIAGNOSIS OF CHRONIC PAIN: CARTESIAN DUALISM, PSYCHOBABBLE AND ARROGANT IGNORANCE

Clinical features of chronic pain can be confusing and difficult to comprehend for the examining physician, leading to the characterization of the patient’s complaints as "non-organic", "psychogenic", "hysterical", "somatizing", and "hypochondriacal", or as evidence of "illness/pain behavior", "emotional overlay", or even malingering.

Especially puzzling is:

 

These features (we now recognize them as classical features of non-nociceptive pain) not only lead to the diagnosis of psychopathology (psychiatric or "functional" illness), but, more importantly, create a poisonous atmosphere in which the patient is blamed for "needing or creating" his pain, and is deprived of the necessary and effective treatment.

Thus, it is imperative to keep in mind that medically unexplained pain - pain with non-anatomical characteristics, or incongruent with observable pathology, is NOT evidence of psychopathology. Frequently, the presence of psychological distress, and the elevated hysteria, hypochondriasis, and depression scales on the MMPI, which are the consequences of pain, are cited as the cause of pain (despite evidence that they normalize with improvement in pain). As well, both the success and failure of psychological treatment are attributed to psychological factors and "illness behavior".

Meanwhile, the challenge should remain for the modern-day Cartesian dualists to provide the empirical evidence and proof that psychopathology causes pain, and, in so doing, to specify the mechanisms by which it does!

It is becoming increasingly apparent that the domain of the psychiatric "somatization" diagnosis is shrinking, as neuroscience keeps expanding our knowledge of NNP (non-nociceptive pain) mechanisms.

We, as physicians, should heed the exhortations of the medical masters, past and present:

"Pain must be regarded as a disease… and the physician’s first duty is action – heroic action – to fight disease". (Benjamin Rush)

"Few things a doctor does are more important than relieving pain… pain is soul destroying. No patient should have to endure intense pain unnecessarily. The quality of mercy is essential to the practice of medicine; here, of all places, it should not be strained". (Marcia Angell)

 

 

 

 

 

 

 

TREATMENT OF CHRONIC PAIN

DRUGS

Historically, two herbs have provided humanity with pain relief: willow and poppy. Even today, 95% of the analgesics in use are derivatives of either ASA or opium.

ASA and NSAIDS are usually the first line approach to the treatment of chronic pain, esp. pain of inflammatory variety. When combined with opioids, they may have a synergistic effect.

ANTIDEPRESSANTS have been used with varying degrees of success. The most commonly used ones are amitriptyline and trazodone, since they also enhance SWS (slow-wave sleep, i.e., stage III and IV of sleep), a feature of particular advantage in treating fibromyalgia (cyproheptadine and zolpidem may be useful in this regard, too). Many other antidepressants have been used, including, more recently, the dopaminergic ones. Bupropion has been found useful in some cases of neuropathic pain.

 

ANTICONVULSANTS gabapentin and lamotrigine are generally used as the first line approach to the neuropathic pain.

GABA agonists are also of considerable value; baclofen – a GABAB agonist – is particularly useful in treatment of spastic pains.

AMPHETAMINES have been used in combination with opioids for treatment of severe, intractable pain.

ALPHA-2 AGONISTS – clonidine – are sometimes extremely effective and highly synergistic when combined with opioids.

SUBSTANCE P ANTAGONISTS have shown a potent analgesic effect in clinical trials, and at least one preparation should be available for general use soon. Interestingly, this same agent has been quite effective as an antidepressant, as well.

CCK ANTAGONISTS – proglumide 200-250 mg p.o. – cancel CCK antagonism to opioids, augments opioid analgesia, and restores opioid effectiveness in neuropathic pain.

NMDA-RECEPTOR ANTAGONISTS

Recognition of NMDA-receptors as mediators of chronic pain has opened up a huge area of research. Drugs that block these receptors have a glorious potential in the treatment of chronic pain, esp. the neuropathic pain. When combined with opioids, they have a synergistic effect, and can restore opioid sensitivity in neuropathic pain.

The currently available agents in N.America are ketamine (I.V. – 0.3mg/kg x 10 min.: substantial reduction in FM pain lasting 7 days), dextromethorphan (10-30 mg/kg B.I.D.), and amantadine, but two very promising agents in wide usage in Europe – flupirtine and memantine – should become available soon. Research on ziconotide – a snail venom derivative – looks extremely promising.

OPIOIDS

The most effective by far, and the most feared and underutilized drugs in the treatment of chronic pain are the opioid analgesics. Prejudice, paranoia and ignorance surrounding these drugs, are the main reasons behind the inadequate treatment of chronic pain and a colossal amount of unnecessary suffering that it causes.

The main effects of opioids (both external and internal) are achieved through stimulation of the mu-opioid receptors. They amount to 70% of the spinal opioid receptors, while the share of delta and kappa receptors is about 25% and 5%, respectively.

The vast majority of opioid receptors in the dorsal horn – about 70% of the total mu-receptors – are located on the pre-synaptic terminals, where they potently inhibit the release of glutamate and substance P from the C-fiber afferents. Post-synaptically, they cause membrane hyperpolarization (preventing the NMDA-receptor activation and the wind-up phenomenon), while also stimulating the inhibitory GABA interneurons.

The loss of pre-synaptic mu-receptors in injured or severed nerves, explains the reduced effectiveness of opioids in neuropathic pain.

Opioid analgesia is usually initiated with the short half-life agents, given q 3-4 h:

Morphine 15-30 mg

Codeine 30-60 mg

Oxycodone 10-15 mg

Hydrocodone 10-15 mg

Hydromorphone 2-4 mg

Caution: CYP 2D6 inhibition reduces the effectiveness of codeine, oxycodone and hydrocodone (preventing formation of active metabolites).

Once the effective drug is found (44% of patients required trials of 2 or more, while 20% required trials of 3 or more opioids), a sustained-release opioid is substituted, in the same daily dosage, given b.i.d. or even o.d.

The 24-hour baseline dose, for sustained release opioids, is:

Morphine 60 mg

Codeine 200 mg

Oxycodone 30 mg

Hydrocodone 40 mg

Hydromorphone 7.5 mg

Methadone 20 mg

Levorphanol 4 mg

Fentanyl 25 microg transdermal patch, lasting 72 hours: equivalent to 45-135 mg/day of oral morphine; doesn’t pass through the liver, less constipation.

 

Oxycodone is the most utilized sustained-release opioid, due to fewer side-effects, easy titration and marked effectiveness in visceral pain (probably by added stimulation of kappa-receptors).

Methadone and levorphanol are opioids with NMDA-antagonist effects, but are difficult to titrate, and exhibit delayed-onset side-effects, esp. sedation.

Every patient on sustained-release agents should be provided with RESCUE MEDICATION – a fast-acting opioid to treat BREAK-THROUGH pain; this may be needed every 2-4 hours, in the dose that is 5-15% of the 24-hour baseline dose of the long-acting opioid.

 

SIDE EFFECTS

The most feared side effects of opioid analgesia are tolerance and addiction – both totally unsubstantiated by clinical evidence. In the vast majority of chronic pain sufferers, tolerance and addiction DO NOT occur. What is encountered more frequently is PSEUDOADDICTION – appropriate demand for adequate pain control.

Once the pain-relief dosage is established, it remains stable; if the disease progresses, or activity increases, titration to a higher stable dose is necessary. If rescue medication becomes unnecessary, or sedation appears, the dose can be slowly reduced.

Inadequately treated pain is a much more important cause of opioid tolerance than use of opioids themselves!

 

 

 

 

 

 

 

 

Other typical side effects are usually resolved within a few days to a week.

Respiratory Depression: clinical evidence shows clearly that this does not occur when the drug is titrated against the patient’s pain.

Nausea/Vomiting: occurs in 10-40% of pts, may require anti-emetics.

Sedation: if intolerable, dose reduction by 25% may be required.

Constipation: may be troublesome in over 50% of pts. Use bulk laxatives.

Pruritus: may require non-sedating anti-histaminics during the first week.

Myoclonus: very rare; benzos (clonazepam) useful.

Side effects – result of the stimulation of non-opioid receptors – can be ingeniously managed by adding a miniscule dose (0.001% of the usual dose) of an opioid antagonist (e.g. naltrexone) to the opioid treatment regimen.

Adding an NMDA or a CCK antagonist, or an alpha-2 adrenergic or GABA agonist, can frequently be effective in reducing the pain-relieving opioid dose.

SENSORY MODULATION

Included here are various interventions that either block or modify the sensory input. These interventions can be quite effective, esp. when combined with adequate drug analgesia. Local anesthetic blocks, including sympathetic blocks, can sometimes provide remarkable relief, lasting days and weeks. Physical and electrical stimulation can be effective, and hypertonic saline injections can sometimes provide long-lasting relief.

PSYCHOLOGICAL INTERVENTIONS

Affective and cognitive dimensions of pain can be manipulated through psychological techniques, thus providing better gate control to the sensory input. CBT has been widely used and found helpful, and so has hypnosis, which can differentially influence the perception of the pain intensity, and the pain unpleasantness. Social support is of paramount importance, too.

PLACEBO

The placebo effect in pain is easier to comprehend if one views pain not as a stimulus, but as a sequence of appropriate motor responses to deal with the noxious stimulus:

  1. Escape – from the noxious source, remove the source
  2. Guard – assume protective posture, immobilize; to allow healing
  3. Seek cure or remedy – go to healers, shamans, physicians

Appropriate action influences the affective-motivational and cognitive-evaluative dimensions of pain, thus potently activating the descending inhibitory controls.

PET and fMRI studies of patients receiving an active drug or a placebo, furnish proof of the placebo effect being mediated by the internal opioid system – showing increased blood flow to the opioid receptors-rich areas in the anterior cingulate and lower brainstem. This effect can be totally blocked by naloxone (opioid antagonist), and attenuated by CCK; on the other hand, it can be augmented by CCK antagonists.

REDEFINING PAIN

With this knowledge, let me elaborate now on a new perspective on pain, and provide a new definition of it.

It is well known that damage to the anterior cingulate cortex (Brodmann’s area 24) abolishes the generation of pain, despite activation of nociceptive pathways ("I feel the pain, but it doesn’t hurt").

Thus, we may assert that pain is an emotion, a construct given by the intrinsic activity of the brain. As such, pain is not localizable; it may seem localized because of co-activation of pain - the emotional state and general tactile stimulation.

"The unpleasantness of pain is an emotional state generated by the brain, not an event that somehow resides at a particular body location" (R.Llinas). This definition clearly implies that sensory pathways do not execute sensations; they only serve to inform the internal context (intrinsic activity of the brain) about the external world. In order to understand the states of pain, and devise more successful modes of pain treatment, it is imperative that we separate the carriers of sensory activity from the actual executors of sensation.

Only through this approach will we be able to avoid perpetuating the noxious errors of Cartesian dualism, and reduce needless suffering of millions of people in chronic pain.

In conclusion, I will reiterate "Few things a doctor does are more important than relieving pain"!

D.Z.FULGOSI, MD, FRCP(C)

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