Pain part 1: introduction to pain

So what is pain?

Pain is defined as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’.² This is an over-simplification of the complex, entirely subjective, sensation with physical and psychological effects. The pain mechanism involves:

The initial sensation (nociception = sensation of pain) is adjunctive to the affective reaction to pain (anxiety, stress, fear) and these cannot be separated from each other, which then leads to behaviour as a result of the pain ‘experience’.

Pain experience is dependent upon age, gender, ethnicity, culture, personality, stress, depression and anxiety. Various settings can affect your pain levels, including whether you are stressed, anxious or tired and whether you trust in your clinician. It is known that soldiers in military zones have higher pain thresholds in combat than off duty; and rugby players continue to score tries even having just sustained a fracture during a tackle!

Pain can be caused by organic and psychological causes. Herta Flor's pain psychology group in Mannheim have eloquently shown, with MRI studies in man,³ that a significant vascular activity in reaction to pain is initiated due to the affective components of pain rather than the physical nociceptive process or actual tissue damage. This is demonstrated by evaluating and comparing the brain activity of a subject's brain whilst experiencing pain elicited by a heat thermode on his/her hand, compared with the brain activity observed when he/she watches a partner undergoing the same experiment. Nearly 60% of the pain-elicited brain active areas were activated when the subject was empathizing rather than directly experiencing pain. This highlights the known role of the affective and emotional components of pain, with 60–80% of brain activity related to the emotional and affective components of pain. This dwarfs the areas directly activated during eliciting physical pain (action potential in peripheral pain nerve–nociceptors – a process referred to as nociception) and sensation (recognition of a painful stimulus when the stimulus is ‘recognized’ by the somatosensory cortex). The dominant aspect of the affective and emotive components of pain, causing the actual behaviour and suffering as a result of the pain experience, provide the most challenging aspect of management of pain conditions.

Over recent times, there have been significant developments in understanding the pain mechanism, the implications of which are spread over many different fields, including: neuro-imaging, psychometrics, neuro-immunity, neurophysiology and pain genetics.⁴ This in part may explain the difficulty in reaching and or maintaining a consensus for the taxonomy of pain itself. Woolf (2010)⁵ eloquently highlights this by posing the question ‘What is this thing we call pain?’ Woolf classifies pain into three groups:

In this paper, it is emphasized that the processes driving these pain types are different and that treatments should be specific and preferably directed at the distinct mechanisms responsible.⁶ Within the orofacial region there has been significant progress in advancing the understanding of musculoskeletal pain and neuropathic pain related to the orofacial region (Figure 1).^7,8,9,10,11

Types of pain⁵

How and where does pain happen?

We now understand that specific pain circuits exist, including general receptors and transmitters at the primary, secondary and tertiary sensory neuron interface play a role in pain (Figure 2).

We understand that the key primary sensory nerves transmitting painful stimuli are A delta (cold and pain) and C fibres (warm and pain). They synapse with the secondary order sensory neurons, a specific region of the spinal cord (lamina I of the distal root ganglion, DRG). These secondary order neurons convey pain to the contra-lateral tertiary sensory neurons in the sensory cortex. Other specific areas of the brain play a role in pain, although their roles are not yet fully understood (thalamus, anterior cingulate cortex, insula and brainstem). However, our comprehension of the mechanisms behind the complex peripheral and central nervous system interaction has only just begun. Translational research methods, including functional MRI, biomolecular and genetic assays, are rapidly improving our ability to research these mechanisms in man. Psychometric studies (social, illness behaviour, psychological distress, beliefs and attitudes, personality traits, drug abuse) will enhance our understanding of the affective components of pain (Figure 2).

Types of orofacial pain

Stages of the pain experience

The pain process involves four key stages:

1. Nociception

Nociception involves:

Tissue damage neuropeptide release;

Chemical and electrical events (conduction);

Activation of the sensory cortex.

Pain signal conduction

Painful stimuli (thermal, mechanical, inflammatory due to infection, radiation, chemical) are sensed by specific thinly myelinated A delta and non-myelinated (slow) C nerve fibres with distinct tactile and proprioceptive receptors. Extreme noxious stimuli are converted to electrical activity by transient receptor potential generating channels (TRP channels) and purinergic channels. This electrical activity is amplified by sodium channels to initiate an action potential in primary sensory neurons. These primary neurons in turn synapse, via glutamate transmitters, with secondary order neurons near the spinal cord in the distal root ganglion (DRG). The second order neurons lie predominantly in the superficial laminae (I and II) in the spinal dorsal horn (Figure 2 a–d).

Dedicated tracts convey specific pain fibres. The lateral spinothalamic tract projects multimodal sensory inputs from spinal wide dynamic range neurons to the lateral thalamus implicated in processing sensory and discriminative aspects of pain. The medial aspect of the spinothalamic tract and the spinoparabrachial tract project to the medial thalamus and limbic system, implicated in the emotional and aversive aspects of pain. Cerebral synapses contain one of the following neurotransmitters: norepinephrine, acetylcholine, or serotonin.

The experience of pain is perceived in the sensory cortex. In addition, there are descending and ascending pathways that may inhibit or facilitate pain (Figure 3a, b). The ‘descending anti-nociceptive tract’ exerts an inhibitory effect on the transmission of the pain signal through its influence within the dorsal root of the spinal cord (Figure 3).

The peripheral nervous system (PNS) involves specific receptors (nociceptors), transmitters, modulators and specific pain nerves C and A delta fibres, causing elicited activity in health (Figure 4) and resulting in:

Inflammation;

Receptors activation;

Axons (primary/secondary/tertiary [cortex]);

Neurotransmission.

The central nervous system (CNS) comprises the spinal cord and brain (Figure 2 a–d). The peripheral and central nervous system events do not occur in isolation. There is constant cross-talk and upward and downward interaction, recognition and modulation.

Pain mediation: chemical mediators of pain

Pain mediators, such as bradykinin, cytokines and serotonin (5-hydroxytryptamine, 5-HT) are specific chemicals that stimulate nociceptors, and are released at the site of tissue damage.^16,17 Most mediators of pain act on intracellular calcium, leading to activation of calcium dependent kinases, for example Cyclo-oxygenase-2 (COX-2) and Nitric oxide synthase (NOS). Prostaglandins are the product of COX-2 activation facilitating neurotransmitter release from primary neurons at the spinal dorsal horn. The combination of mediators and prostaglandins at the site of tissue trauma is sometimes referred to as ‘inflammatory soup’ (Figure 5). These chemical mediators are an extremely important component of the pain experience, as they constitute the initiation of the pain cascade. As such, its inhibition or suppression could have a significant effect on limiting the pain experience (Figure 5).¹⁸

The central nervous system is constructed of the brain and spinal cord and its constant interaction with the peripheral nervous system (PNS) is continual and reciprocal. The complex interactions between the PNS and CNS far exceed the traditional concept of the nervous system functioning like an ‘electrical system’. Any trauma peripherally will result in immediate and ongoing interactions between the PNS and CNS. Should persistent irritation (infection for example) occur peripherally, lasting more than 3 months, permanent changes take place within the sensory cortex as a result. In addition, the majority of local inflammation, arising after skin trauma, is neuroinflammation rather than cellular, illustrating the link between the nervous and the immune systems. A simplified overview of the PNS and CNS is illustrated in Figures 2, 3 and 4.

Genetics in pain

Genetics may play a role in all of the above and, in the past five years, knowledge has increased in relation to genetic deficiencies in specific pain receptors and how preponderance of expression of various transmitters will affect the patient's pain experience.²⁰ Humans have 3.16 billion base-pairs of DNA and 23 pairs of chromosomes. The Human Genome Project has sequenced about 2.8 billion base-pairs to date and only 3% of the human genome actually code for proteins (actually doing the work!), with approximately 15% of the non-coding DNA in humans being conserved (presumably of functional importance). The rest of the genome is presumed to be a bit like your attic full of stuff that may be useful one day! But the exact role of this apparently redundant DNA has yet to be revealed. With regard to specific pain-related genes (Table 1),^{19,20,21,22,23,24,25,26,27} SCN9A gene polymorphism, resulting in Nav 1.7 sodium channel deficiency, resulting in total lack of pain perception, was identified in six children from three related Pakistani families who feel no physical pain. Although capable of feeling other sensations like warm and cold, they have a lack of pain perception and suffered injuries as follows:

The COMT protein (catechol-O-methyl transferase) is a brain janitor and metabolizes the brain chemicals called dopamine and norepinephrine. Dopamine is often known as the brain's ‘pleasure chemical’, because of its role in transmitting signals related to pleasurable experiences. Differences in expression of this gene determined differences in pain directions experienced by patients.¹⁹

Melanocortin 1 receptor deficiency linked to Muopoid receptor deficiency seen in redheads may be related to a 20% increase in pain thresholds. It does appear that redheads have a significantly different pain threshold and require less anaesthetic to block out certain pains.²⁰

A recent review of ‘neurogenetics’ summarizes some of the surprising aspects in highlighting the underlying susceptibility of certain individuals in developing chronic persistent pain.²⁸

Modulation of pain

Once the pain information is in the brain, the processing paradigm is not yet clear. Reflex pathway signals go to the motor cortex, then down through the spinal cord and to the motor nerves causing muscle contractions. Ronald Melzack and Patrick Wall proposed that a gating mechanism exists within the dorsal horn of the spinal cord that downwardly inhibits pain. Small nerve fibres (pain receptors) and large nerve fibres (‘normal’ receptors) synapse on projection cells, which go up the spinothalamic tract to the brain, and inhibitory interneurons within the dorsal horn causing inhibition of the ascending pathways of pain. However, several recent observations have led scientists to think that the brain can influence pain perception.^18,29

The pain from the cut on your hand eventually subsides or reduces to a lower intensity. However, if you consciously distract yourself, you don't think about the pain and it bothers you less. People given placebos for pain control often report that the pain ceases or diminishes.

This indicates that pain-influencing neural pathways must exist from the brain downward with an inhibition of sensory input whilst simultaneously facilitating inhibitory neurones (Figure 3).¹⁸

The descending pathways originate in the prefrontal cortex (via the thalamus) and the hypothalamus. Thalamic neurons descend to the midbrain to the periaqueductal gray (PAG), where they synapse on ascending pathways in the medulla and spinal cord and inhibit ascending nerve signals. This inhibits pain relay, thus providing pain relief (analgesia). Some of this relief comes from the stimulation of natural pain-relieving opiate neurotransmitters called endorphins, dynorphins and enkephalins.¹⁸

Pain signals can set off autonomic nervous system pathways as they pass through the medulla, causing increased heart rate and blood pressure, rapid breathing and sweating. The extent of these reactions depends upon the intensity of pain, and they can be depressed by brain centres in the cortex through various descending pathways. As the ascending pain pathways travel through the spinal cord and medulla, they can also be set off by neuropathic pain – damage to peripheral nerves, spinal cord or the brain itself. However, the extent of the damage may limit the reaction of the brain's descending pathways. The influences of the descending pathways may play a role in neuropathic/psychogenic pain (pain perception with no obvious physical cause). Identified regions of the brain active in pain modulation are illustrated in Figure 3.¹⁸ Cognitive factors (eg expectations) impact pain via the prefrontal cortex (PFC) that modulates the activity in pain-related brain regions. The PFC has, for instance, been shown to modulate the activation of the anterior cingulate cortex (ACC) but might also target connections between brain regions associated with pain perception. The primary sensory cortex (SI), the secondary somatosensory cortex (SII) and the periaqueductal grey (PAG) activity can all be modulated by PFC, hippocampal and ACC activity which will drive the behavioural and suffering activity by the patient.¹⁸

However, more recently, the anterior cingulate cortex (ACC) has been identified as the ‘attentional focus’ for pain. Neuro-imaging and electrophysiological studies in humans have shown that somatosensory stimuli, including those causing pain, activate ACC neurons and other related limbic areas.^29,30 Recent studies have demonstrated that rostral anterior cingulate cortex responses were higher for the strong placebo effects, thus mirroring the behavioural effects. The activity of the ACC may directly link placebo analgesia to anticipatory activity in the ventral striatum, a region involved in reward processing, reinforcing the rostral ACC activity correlating with increasing analgesic efficacy.³¹

In another recent study assessing personality traits and placebo effects, molecular imaging showed that subjects scoring with positive trait measures presented greater placebo-induced activation of μ-opioid neurotransmission in the subgenual and dorsal anterior cingulate cortex (ACC), orbitofrontal cortex, insula, nucleus accumbens, amygdala and periaqueductal grey (PAG).³² In addition, endogenous opioid release in the dorsal ACC and PAG was positively correlated with placebo-induced reductions in pain ratings (Figure 3).

Another MRI imaging development is the assessment of functional connectivity differences between brain regions, which might identify some of the earliest functional consequences of a disease process. Based on this method, some studies claim that they can predict the patient's placebo response.

Even though the function of the grey matter is unclear, there is increasing evidence that significant changes in grey matter may predispose the patient to the development of chronic pain. However, the jury remains ‘out’ as to whether this is a response to the pain.³¹

There is also a second pain pathway that regulates our rapid unconscious experiences of pain, the autonomic nervous system. Most of this engages the inappropriately named ‘fight-or-flight’ circuit via the amygdala. Signals are relayed to a few separate areas such as the cingulate (that processes conflict) and the insula (that appears to do everything). It is thought that these areas regulate the emotional salience of pain.^18,31

Conclusion

Clinicians must have an understanding of the complexity of the different pain conditions to optimize their patient care.

This section has hopefully highlighted how complex pain is for both patients and clinicians. Pain can be a result of emotional or physical pain and, if prolonged, become a disease itself of the ‘pain matrix’ resulting in neuropathic and dysfunctional pain. The majority of the pain response is due to the emotional and affective components of the pain response, driving behaviour and suffering of the patient. A minute, but significant, part of the pain process is the healthy inflammatory and nociceptive pain which is designed to protect us (the bit we understand). Additional challenges are that the pain ‘system’ involves constant exchange of information (both electrical and chemical) between the peripheral and central nervous system, and a constant ‘moving target’.

The trigeminal nerve, the cranial sensory nerve, provides the primordial sensory system, which is designed to protect our airways, mind, senses of sight, hearing, smell and taste, and our alimentary entrance, all functions that underpin our very existence. Is it any wonder that challenges to this region result in massive fear, anxiety and stress responses, hard wired by our neurophysiological system supporting our survival?

Because of these features, pain must be managed by treating the patient holistically and not just by prescribing drugs that target explicit parts of a known pathway. Empathy and acknowledgement of the patient's problem are probably the most powerful components to successful management of chronic pain patients, reflecting the affective and emotional activity in response to pain.

The future is to tap into our own pain modulation systems. Pain suppression is an inherent skill; think of the rugby player with a broken leg continuing to score a try or a self-immolating Tibetan monk! Sleep is the ultimate ubiquitous suppressor of any input to the brain; if only we could harness part of this potential. Perhaps we could train ourselves and our patients to manage pain by using hypnosis, acupuncture or meditation to maximize pain modulation or other yet unknown techniques?