Chronic pain mechanisms

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3 Chronic pain mechanisms

This chapter looks at some of the definitions and talks about the triggers that may result in chronic pelvic pain (CPP) and some of the predisposition and maintenance factors that may place an individual at risk for developing CPP. Whereas these triggers, predisposing and maintenance factors will have a biological basis, we also have to consider the biological basis of the pain mechanisms, acute and chronic, in their own right.

Defining chronic pelvic pain

Several groups have tried to tackle the issue of defining CPP and discussions are ongoing. The Urogenital Pain Special Interest Group of The International Association for the Study of Pain (IASP) are currently proposing the following:

Chronic Pelvic Pain is chronic/persistent pain perceived * in structures related to the pelvis of either men or women. It is often associated with negative cognitive, behavioural, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction.

^* Perceived indicates that the patient and clinician, to the best of their ability from the history, examination and investigations (where appropriate), have localized the pain as being perceived in the anatomical pelvic area.

They go on to say:

In the case of documented nociceptive pain that becomes chronic/persistent through time, pain must have been continuous or recurrent for at least 6 months. That is it can be cyclical over a six month period, such as the cyclical pain of dysmenorrhoea. Six months is arbitrary; however, six months was chosen because three months was not considered long enough if we include cyclical pain conditions. If non-acute and central sensitization pain mechanisms are well documented, then the pain may be regarded as chronic, irrespective of the time period.

Chronic Pelvic Pain may be subdivided into those conditions with well defined classical pathology (such as infection and cancer) and those where no obvious pathology are found.

For the purpose of this classification the terms Specific Disease Associated Pelvic Pain is proposed for the former and Chronic Pelvic Pain Syndrome is used for the latter.

Chronic Pelvic Pain Syndrome definition

Chronic Pelvic Pain Syndrome (CPPS) is the occurrence of chronic pelvic pain where there is no proven infection or other obvious local pathology that may account for the pain. It is often associated with negative cognitive, behavioural, sexual and emotional consequences as well as with symptoms suggestive of lower urinary tract, sexual, bowel or gynaecological dysfunction.

CPPS is a subdivision of Chronic Pelvic Pain (see above).

The implications of the above for clinical management are huge. Essentially pain perceived to be both chronic and sited within the pelvis is associated with a wide range of causes and associated symptoms that must be investigated and managed in their own right. For this to occur, patients with CPP must have access to the appropriate resources through multispeciality (e.g. urology, urogynaecology, gynaecology, neurology and pain medicine) and multidisciplinary (e.g. medical doctor, nurse, psychology and physiotherapy) teams (Baranowski et al. 2008b) (see Chapter 8.1).

Chronic pelvic pain syndrome: The cause

It is important to realize the difference between trigger, predisposition and maintenance factors and how these may relate to the mechanism for the perceived pain and associated other symptoms.

Over the years there has been a great emphasis on the triggers for the chronic pain and much work has focused on local pathology, such as infection and local irritation with inflammation. This has resulted in a number of inappropriate outcomes (Abrams et al. 2006, Baranowski 2008a):

1. Over-investigation of the end-organ as the source of pain;

2. Inappropriate treatment of the end-organ (e.g. the overuse of antibiotics and even the removal of organs);

3. A spurious classification system that encourages the above.

A small group of patients may be able to identify the exact trigger. However, in many ways triggers are not important, as they are probably numerous, transient and can not be avoided. Ongoing and repeated investigations for the ‘cause’ are associated with a worse prognosis.

Triggers do not result in CPPS in all persons, though the proportion is unknown. It is now accepted that as well as triggers we need to consider predisposing factors and maintenance factors.

Genetics may play a role in predisposing patients to chronic pain, though the exact nature is not fully worked out. Other predisposing factors may include childhood experiences, negative sexual encounters and sexual violence, stress and other social factors, personality traits, as well as physical disability and medical illness. Some of these factors as well as precipitating inappropriate pain responses may also maintain the pain once started.

Maintenance is thus a complex issue. All chronic pain is associated with emotional and behavioural consequences (Sullivan et al. 2006, Nickel et al. 2008). The perceived severity of the pain understandably will be a major decisive factor as to how distressed and disabled the patient is. However, there is a cycle of events, where depression and catastrophizing are poor prognostic factors in their own right and clinical experience suggests that if these issues are not managed no progress in managing the pain will be made. Issues with work, relationships, sex and loss of meaning of life also appear to be as important. All of these factors can produce inappropriate maladaptive coping mechanisms such as inappropriate pain-contingent resting cycling with overactivity and as a result widespread total body pain, increased disability and increased distress.

Chronic pelvic pain syndrome: The mechanisms

There are many texts describing the mechanisms of chronic pain at a cellular level and neurobiological level (Vecchiet et al. 1992, Pezet & McMahon 2006, Nickel et al. 2008). The mechanisms for somatic, visceral and neurological tissue may overlap, but there are some important differences. As well as this science being applied to the patient the biopsychosocial model alluded to above needs to be integrated into the model.

All the structures within the pelvis and some outside of the pelvis (e.g. thoracolumbar junction) may, when stimulated, result in pain perceived in the pelvis. Recurrent activation of the nervous system may be associated with both peripheral and central sensitization.

The main consequences of the above science for the clinician are:

1. Lower threshold activation of peripheral nociceptors with increased pain perception;

2. Increased receptive field;

3. Patients become aware of stimuli not normally perceived – hyperaesthesia;

4. Stimuli that are normally not painful become perceived as painful – allodynia;

5. Cross-over hypersensitivity occurs (viscero-visceral hyperalgesia, visceromuscular hyperalgesia);

6. Central-mediated functional abnormalities of the viscera (e.g. abnormal function of the bowel with alternating diarrhoea and constipation);

7. Central-mediated changes in peripheral structure (e.g. Hunner’s ulcers, peripheral oedema and change in vasculature);

8. Neurobiological psychological consequences.

(Vecchiet et al. 1992; Giamberardino 2005; Pezet & McMahon 2006; Baranowski et al. 2008b).

A case history may best illustrate these points:

A patient develops an acute cystitis, infection may never be proven and stress, increased pelvic floor muscle tension is a possible cause for the initial symptoms. Perhaps there is a background of a negative sexual encounter (often there is not) and predisposing genetics, The ongoing pain results in central sensitization involving excitatory amino acid receptors such as N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole epropionic acid (AMPA). The patient feels that their bladder is never empty (aware of stimuli not normally perceived), and holding on to their urine produces pain (stimuli that are normally not painful become perceived as painful). Investigations of the bladder do not reveal infection, but the bladder is inflamed and swollen (central-mediated changes in peripheral structure). The pain appears to spread and the vulvar region becomes very sensitive with evidence of allodynia (increased receptive field). The patient describes erratic bowel habit, this may be due to the treatment; however, irritable-bowel-type symptoms due to central-mediated functional abnormalities of the viscera are also a possibility. The patient develops muscular pain (partly due to visceromuscular hyperalgesia but also due to inappropriate resting and cycles of over- and underactivity). As you might expect, depression, anxiety and anger set in; much of this may be secondary to the low quality of life and the pain but physical neurobiological changes may also be involved.

The initial trigger may involve any structure: somatic (cutaneous/muscular), visceral or neurological. The symptoms may remain well focused in that area, such as in the organ-based pain syndromes (e.g. bladder pain syndrome, vulvar pain syndrome, testicular pain syndrome) or in a specific muscle or local group of muscles. A patient may present at any stage in the above story and with a focus of pain within either a single or multiple system(s)/organ(s). The balance between afferent and efferent (functional) abnormalities is not linear and as a consequence some patients may present with primarily sensory and others with primarily functional phenomena. Patients may present with primarily pain perceived in one area and functional abnormalities in another. As well as these changes occurring or perceived within the pelvis, symptoms may be found elsewhere. For instance, bladder pain syndrome is associated with Sjögren’s and many pelvic pain conditions are associated with endocrine and immune deficiency as well as fibromyalgia and chronic fatigue syndrome (Abrams et al. 2006).

Mechanisms for chronic pelvic pain

Chronic pelvic pain mechanisms may involve:

1. Ongoing acute pain mechanisms (Linley et al. 2010) (such as those associated with inflammation or infection) – which may involve somatic or visceral tissue. This chapter will concentrate primarily on the visceral pain mechanisms;

2. Chronic pain mechanisms, which especially involve the central nervous system (McMahon et al. 1995);

3. Emotional, cognitive, behavioural and sexual responses and mechanisms (Binik & Bergeron 2001, Tripp et al. 2006). These will be covered in Chapter 4.

Table 3.1 illustrates some of the differences between the somatic and visceral pain mechanisms. They underlie some of the mechanisms that may produce the classical features of visceral pain; in particular, the referred pain and the referred hyperalgesias.

Table 3.1 Comparison between visceral and somatic pain

	Visceral pain	Somatic pain
Effective painful stimuli	Stretching and distension, producing poorly localized pain	Mechanical, thermal, chemical and electrical stimuli, producing well-localized pain
Summation	Widespread stimulation produces a significantly magnified pain	Widespread stimulation produces a modest increase in pain
Autonomic involvement	Autonomic features (e.g. nausea and sweating) frequently present	Autonomic features less frequent
Referred pain	Pain perceived at a site distant to the cause of the pain is common	Pain is well-localized
Referred hyperalgesia	Referred cutaneous and muscle hyperalgesia common, as is involvement of other viscera. This is very important (see below)	Hyperalgesia tends to be localized
Innervation	Low-density, unmyelinated C fibres and thinly myelinated A fibres	Dense innervation with a wide range of nerve fibres
Primary afferent physiology	Intensity coding. As stimulation increases afferent firing increases with an increase in sensation and ultimately pain	Two-fibre coding. Separate fibres for pain and normal sensation
Silent afferents	50–90% of visceral afferents are silent until the time they are switched on. These fibres are very important in the central sensitization process	Silent afferents present in lower proportions
Central mechanisms	Play an important part in the hyperalgesias, viscerovisceral, visceromuscular and musculovisceral hyperalgesias. Sensations not normally perceived become perceived and non-noxious sensations become painful	Responsible for the allodynia and hyperalgesia of chronic somatic pain
Abnormalities of function	Central mechanisms associated with visceral pain may be responsible for organ dysfunction (see below)	Somatic pain associated with somatic dysfunction
Central pathways and representation	As well as classical pathways, there is evidence for a separate dorsal horn pathway and central representation	Classical pain pathways

Ongoing peripheral visceral pain mechanisms as a cause of chronic pelvic pain

In most cases of chronic pelvic pain ongoing tissue trauma, inflammation or infection are not present (Hanno et al. 2005, Abrams et al. 2006, Baranowski et al. 2008a). However, conditions that produce recurrent trauma, infection or ongoing inflammation may result in CPP in a small proportion of cases. It is for this reason that the early stages of assessment will include looking for these pathologies (Van de Merwe & Nordling 2006, Fall et al. 2010). Once excluded, ongoing investigations for these causes are rarely helpful and indeed may be detrimental.

When acute pain mechanisms are activated by a nociceptive event, as well as direct activation of the peripheral nociceptor transducers, sensitization of those transducers may also occur, magnifying the afferent signalling. Afferents that are not normally active may also become activated by the change, that is there may be activation of the so-called silent afferents. Whereas these are mechanisms of acute pain the increased afferent barrage of impulses underlie the mechanisms for chronic pain where the increased afferent signalling is often a trigger for the chronic pain mechanisms that maintain the perception of pain in the absence of ongoing peripheral pathology (see below) (Vecchiet et al. 1992).

There are a number of mechanisms by which the peripheral transducers may exhibit an increase in sensibility.

1. Modification of the peripheral tissue, which may result in the transducers being more exposed to peripheral stimulation.

2. There may be an increase in the chemicals that stimulate the receptors of the transducers (Pezet & McMahon 2006).

3. There are many modifications in the receptors that result in them being more sensitive.

In general the effect of 1 and 2 is to lower threshold and of 3 to increase responsiveness.

Some of the chemicals responsible for the above changes may be released from those cells associated with inflammation, but the peripheral nervous system may also release chemicals in the form of positive and inhibitory loops (Cevero & Laird 2004).

Nerve growth factor (NGF) is an important trophic factor necessary during development for the growth and survival of sympathetic neurons, sensory neurons and neurons in the central nervous system. Associated with local tissue trauma, mast cells, macrophages, keratinocytes and T cells all release NGF, which can then interact with its receptors, TrkA, on nerve endings. It may both directly activate primary afferents but also indirectly such as through the use of bradykinin (Petersen et al. 1998). The result is an increase in response of the primary afferent with multiple action potentials being generated in response to a stimulus as opposed to one or two. The TrkA–NGF complex formed on the afferent neuron may also be transmitted centrally where it may alter gene expression. Such long-term gene modification may underlie some of the mechanisms of chronic NGF-induced hypersensitivity.

Adenosine triphosphate (ATP) is thought to be released in increased amounts from certain viscera when stimulated by noxious stimuli. As well as this increased ATP producing an increased stimulation of ATP receptors, when inflammation is present the ATP receptors have their properties changed so that there is an increased response per unit of ATP contributing to the nociceptor activation. ATP is thought to act on P2X3 purine receptors which are found on visceral afferents and small-diameter dorsal root ganglion neurons.

Substance P and other neurokinins (McMahon & Jones 2004) act on afferent tachykinin receptors, such as TRPV1 a transducer for noxious heat and protons, and are thought to play a primary role in inflammatory hyperalgesia. In particular, possibly due to proto-oncogene activation, inflammation is associated with an increase in TRPV1 channel density. As well as this, inflammation may also change the sensitivity of the channel so that it is activated at thresholds that would normally be subliminal. For instance, it has been suggested that this receptor for heat pain may be activated at normal body temperature. Substance P may be released from small fibre afferent neurons as a part of an antidromic response, but there may also be direct mechanisms involving direct depolarization of the nerve terminals.

Voltage-gated ion channels (such as tetrodotoxin-resistant sodium channel, NaV1.8) are also implicated in peripheral sensitization. These channels open or close in response to changes in membrane potential. The voltage-gated sodium channel is a complex channel with multiple subunits. The alpha subunit contains the voltage sensor and the ion channel. The alpha subunit is composed of a number of alpha subunit variants that affect its sensitivity to changes in the membrane potential and will also alter ion flow. Changes in these alpha subunits may thus sensitize the neuron associated with the channel. The beta subunit is also considered important by an effect on the action potential as well as by other possible mechanisms. Changes in potassium and calcium voltage-gated channels may also underlie a part of the mechanism responsible for peripheral sensitization.

Second messenger pathways within the primary afferents enable amplification of peripheral singles. In general these pathways are balanced out by others that are responsible for reducing any activation. During chronic pain these mechanisms may become imbalanced. Classical second messengers signalling pathways involve protein kinase which via an elaborate series of chemical activations cause a release of calcium within the neuron. There are probably a number of other mechanisms that may also release calcium, and nitric oxide has been implicated in some of these. As well as producing rapid-onset short-lived changes, activation of this messenger system may produce longer-term changes via alterations of transcription and translation at a genetic level.

Spinal mechanisms of visceral pain and sensitization: Central sensitization (Roza et al. 1998, Giamberardino 2005)

The above mechanisms illustrate some of the mechanisms behind peripheral sensitization. These mechanisms and the recruitment of previously silent nociceptive neurons may be maintained even after injury has healed. As a consequence, ongoing nociceptive information may continue arriving at the spinal cord despite no peripheral ‘pathology’. The large ongoing stimulus provided by these mechanisms may then result in a long-term increase in the excitability of the dorsal horn neurons. The mechanisms responsible for this increased excitability produce what is known as central sensitization. Once established central sensitization may be self-perpetuating even if the ongoing peripheral signalling stops or may be maintained by low-threshold fibre activation, e.g. light touch (allodynia).

There are essentially three processes at the spinal cord level that are probably involved in central sensitization. Changes in existing protein activity (post-translational processing) will be the earliest changes (minutes); however, changes in genetic transcription of proteins and even structural changes in neuron connectivity may also have roles to play. These latter changes may occur within days (Nazif et al. 2007).

The chemicals involved in the early phase include a number of neurotransmitters including glutamate, substance P, calcitonin gene-related peptide, prostaglandin E2 (PGE2) and brain-derived neurotrophic factor (BDNF) as well as many others (Cevero & Laird 2004).

Glutamate is an important agent in this process. Increased levels of glutamate, due to recurrent afferent nociceptive fibre activity, remove the magnesium ion block of NMDA. This allows calcium ions to enter the primary afferent with enhanced depolarization. Glutamate also binds to AMPA, which may be another pathway by which it increases intracellular calcium. Other transmitters/modulators released centrally include substance P acting on neural kinin receptors, PGE2 combining to endogenous prostanoid receptors and BDNF acting on tyrosine kinase B receptors which may also increase intracellular calcium. In this situation the calcium ions act to lower the threshold for second-order neuron firing with increased signalling being transmitted to the higher centres.

The second importance of this increase in calcium ions is in post-translational processing; this usually involves the addition of phosphate groups to some of the protein’s amino acids, by enzymes known as kinases. It is the increase in calcium through the above mechanisms that activates these kinases. Phosphorylation can dramatically alter the properties of a protein, typically lowering the threshold at which channels open but also the channel remains open for longer. The result is that a stimulus produces a magnified evoked response.

Visceral hyperalgesia

Central sensitization (Nazif et al. 2007) is responsible for a decrease in threshold and increase in response duration and magnitude of dorsal horn neurons. It is associated with an expansion of the receptive field. As a result it increases signalling to the central nervous system and effects what we perceive from a peripheral stimulus. As an example, for cutaneous stimuli light touch would not normally produce pain. When central sensitization is present light touch may be perceived as painful (allodynia). In visceral hyperalgesia (so called because the afferents are primarily small-fibre), visceral stimuli that are normally subthreshold and not usually perceived may be perceived; for instance, with central sensitization, stimuli that are normally subthreshold may result in a sensation of fullness and a need to void the bladder or to defecate. Stimuli normally perceived may be interpreted as painful and stimuli that are normally noxious may be magnified (true hyperalgesia) with an increased perception of pain. As a consequence, one can see that many of the symptoms of the bladder pain syndrome (formally known as interstitial cystitis) and irritable bowel syndrome may be explained by central sensitization. A similar explanation exists for the muscle pain of fibromyalgia.

Supraspinal modulation of pain perception

It is important to appreciate that nociception is the process of transmitting to those centres involved in perception information about a stimulus that has the potential to cause tissue damage. Pain is far more complex and involves the perception of a nociceptive event but also the emotional response (Rabin et al. 2000). Pain is defined by IASP as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ (Merskey & Bogduk 1994). Modulation of nociceptive pathways may occur throughout the whole of the neuroaxis (spinal cord through to higher centre) and in the periphery and spinal cord involves the mechanisms described above. The brain may also effect the modulation at spinal cord level.

Higher-centre modulation of spinal nociceptive pathways

It is now well-accepted that there are both descending pain-inhibitory and descending pain-facilitatory pathways that originate from the brain (Melzack et al. 2001). The midbrain periaqueductal grey (PAG), just below the thalamus, plays an important part in spinal modulation. It receives inputs from those centres associated with thought and emotion. Projections from the PAG (via several relay systems) to the dorsal horn can inhibit nociceptive messages from reaching conscious perception by spinal mechanisms. The PAG and its associated centres may also be involved in ‘diffuse noxious inhibitory controls’ (DNIC). DNIC is when a nociceptive stimulus in an area well away from the receptive fields of a second nociceptive stimulus can prevent or reduce pain from that second area. This is thought to be the mechanism for the paradigm of counterirritation.

Several neurotransmitters and neuromodulators are involved in descending pain-inhibitory pathways. The main contenders are the opioids, 5-hydroxytryptamine and noradrenaline (norepinephrine).

The pathways and chemicals for the facilitatory modulation are even less well understood, but the mechanisms are well accepted.