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Pain Management

Overview:

Definition:

Pain is described by the International Association for the Study of Pain (IASP) as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage”. 

 

Pain is not only physical:

The perception of pain is so subjective and variable among patients. In order to make sense of the phenomenon, Cicely Saunders, a pioneer in UK hospice movements, brought in the concept of "total pain" in the 1960's. The theory addresses that pain is not only a form of suffering following physical injury(ies), but is also associated with the emotional and spiritual wellbeing of individuals. Her idea was a success and has transformed the practice of pain medicine, principally in the multi-disciplinary (MDT) management of chronic and palliative-care pain patients.

Classification:

Pain is classified by its duration (acute/chronic/acute-on-chronic) and nature (nociceptive/non-nociceptive)

 

Acute versus chronic pain:

Acute pain is transient (i.e. less than 12 weeks in duration) and usually of an identifiable cause.

Post-operative pain from surgical incisions (in descending order of intensity: upper abdomen, thoracotomy, lower abdomen, limbs) and complications (e.g. wound infection, sepsis and abdominal distension) forms the major source of acute pain in hospital. The other potential causes include acute myocardial infarction, pancreatitis, ureteric colic, first-to-second degree burns and trauma.

Most inadequately treated acute pain may evolve into chronic pain, which by definition, lasts much longer and is "beyond the normal expected healing time for the injury". The nature and intensity of the original pain may vary due to the “wind-up phenomenon” and “peripheral or central sensitization”.

 

Nociceptive versus neuropathic pain:

Nociceptive pain arises from any "actual or threatened damage to non-neural tissue and is due to activation of nociceptors". The understanding of which shall require acquaintance of the four key stages of the pain pathway, pain fibres and the rexed laminae.

Neuropathic pain is resulted from “a lesion or disease of the somatosensory nervous system”. The disease process could happen centrally (e.g. multiple sclerosis, spinal cord pathologies) or peripherally (e.g. trigeminal neuralgia, post-herpetic neuralgia, diabetic- and post-traumatic neuropathies). We may further classify neuropathic pain by the aetiology of disease (e.g. over-pressure, degeneration, infection or inflammatory changes of the neuronal structures) and by the involvement of sympathetic nervous system (e.g. complex regional pain syndromes).



Basic sciences:

Axons in the peripheral nervous system:

The peripheral nerves are made up of a collection of nerve bundles with axons embedded in them. These axons are present in three major forms – A, B and C fibres. Their structures and functions are summarized below:



Students are reminded about the overlapping of functions between some peripheral nerve fibres.

 

Key points:

  • Aγ and a proportion of Aα are efferent fibres that relay motor functions
  • Aβ together with some AαAδ and C form afferent fibres to detect innocuous stimuli
  • Most Aδ and C are afferent pain fibres which are activated at much higher threshold than receptors responsible for inocuous stimuli:
    • Aδ fibres form the lateral spinothalamic (neo-spinothalamic) tract which conducts the immediate sharp, pin-prick sensation and the discriminative aspects (e.g. site, intensity, duration) of pain.
    • C fibres form the medial spinothalamic (paleo-spinothalamic) tract which transmits “slow pain” that feels sore and poorly delineated. It also influences the emotional, behavioral and autonomic responses to pain, hence, the changes in heart rate, blood pressure, sweating, gastrointestinal and genitourinary functions.

 

The Rexed Laminae:

The grey matter of the spinal cord is divided into 10 functional layers – the Rexed Laminae. A clear understanding to laminae 1- 5 and 10 is crucial in pain medicine.

Laminae 1 to 5 are located in the dorsal horn and they are served as the main sites of synapse between the first- and second-order afferent neurons.

During a simple synapse, an action potential normally activates the voltage-gated calcium channel at the presynaptic cleft. The influx of calcium ions into the terminus of neuron potentiates exocytosis of neurotransmitters into the synaptic cleft, and by means of passive diffusion, the neurotransmitters may bind to their post-synaptic receptors to cause electropotential changes in the second-order neuron(s). Depending on the nature of the neurotransmitters, these changes could be excitatory (e.g. glutamate, substance P), inhibitory (e.g. GABA) or modulatory (e.g. noradrenaline, serotonin, opioids).

The second-order neurons are composed of three important cell types:

  • Lamina 1 is made up of cells that are predominantly nociceptive specific (NS)
  • Laminae 3-4 consist of low-thresholds (LT) cells that detect innocuous stimuli
  • Lamina 5 hosts mostly wide dynamic range (WDR) cells and they are able to receive both noxious and innocuous stimuli from primary afferents.
  • *Lamina 2 is made up of NS and WDR cells 

 

Putting Rexed laminae into application:

    1. What do we already know?

    Aδ fibres synapse at laminae 1 and 5; C fibres at 1 and 2.

    2. What does histological evidence show?

    Evidence suggests that cells in lamina 2 are showing considerable dendritic linkages between laminae 1, 5 and the rest of dorsal horn

    3. What can we conclusion from the above?

    An overwhelming Aβ signals produced by actions e.g. rubbing over the affected skin of pain, transcutaneous electrical nerve stimulation (TENS) could dampen the transmission of pain via Aδ and C to the higher center (See "Gate-control theory" by Melzack and Wall for further details).

    Pathophysiology:

    The important stages of the pain pathway are transduction, transmission, perception and modulation. This model is particularly useful for the appreciation of the underlying mechanisms in acute pain.



    Transduction:

    Tissue damage triggers the release of “a soup of” pain and inflammatory mediators around the site of injury (e.g. prostaglandins, leukotrienes, substance P, mast cells, histamine, H+, K+, acetylcholine). These substances sensitize the surrounding nociceptors and activate their voltage-gated sodium channels.

     

    Peripheral transmission:

    Following successful depolarization, action potentials normally propagate along the axon; through the dorsal root ganglion (DRG), lissauer’s tract and into the dorsal horn for synapse at the rexed laminae.

    The route of pain transmission “above the neck” is dissimilar to the above. Their nociceptive impulses are united at the trigeminal ganglion and then relayed to the medulla for synapse with the higher center.

     

    Central transmission and perception of pain in the higher centre:

    The three major ascending tracts that mediate pain from the periphery to high centers are named as follows:

    1. Neo-spinothalamic (lateral spinothalamic) tract
    2. Paleo-spinothalamic (medial spinothalamic) tract
    3. Archi-spinothalamic tract

    Neo-spinothalamic tract forms a “direct connection” with the thalamic nuclei and sensory cortex of the brain, hence, provides the fast and pinprick sensations of pain immediately following the injury.

    The other two ascending tracts tend to give off “collaterals” to the brainstem, thalamus and other cortical area as they ascend along the spinal cord:

    Paleo-spinothalamic tract transmits the slow and dull characteristics of pain. It also stimulates brainstem nuclei to activate the descending pathway for pain modulation. 

    Archi-spinothalamic tract has collaterals that innervate hypothalamus and the limbic system. It is so predicted by experts that this tract could infleuence autonomic nervous system; and also the emotional and behavioral responses to pain.

     

    Modulation and the descending pathways of pain:

    This is rather complex and is thought to occur at multi-level. To simplify, the modulation of pain mostly occurs:

    • Between afferents within the dorsal horn (re: the Gate-control theory)
    • Supraspinally from the descending pathways initiated at the higher centre.

    The principal brainstem nuclei contributory to the descending tracts are the peri-aqueduct grey (PAG) matter, locus coeruleus (LC) and nucleus raphae magnus (NRM).

    PAG activates the serotonergic (5-HT) pathway of NRM. Together with the noradrenergic pathway of LC, their projections descend along the dorsal horn to interact with the primary nociceptive- and inter-neurons.

    The modulatory substances that these fibres release, mostly in form of opioids and serotonin, are suggested to prevent the transmission of pain by inhibiting exocytosis of neurotransmitters from the primary-order neurons. 

    The remaining contents of the descending tracts are hypothesised to excite interneurons at rexed lamina 2, a.k.a. substantial gelatinosa, and thus to cause interruptions of pain transmission between laminae 1 and 5. 

        Management:

        A statisfactory pain regimen would require:

        • identification and treatment of reversible causes e.g. bowel obstruction, dislocation
        • emotional support e.g. reassurance, relaxation, distraction, behavioural modification
        • implementation of a stepwise, multi-modal analgesic approach e.g. WHO pain ladder
        • possible referral to the pain management team

         

            Pharmacology:

            The essence of pain management is to achieve "balanced analgesia" – an approach that maximizes therapeutic benefits of a combination of analgesic agents at their lowest possible doses, thereby to reduce side effects.

            Rosalind Haire has produced some useful revision notes on "analgesics" in the prescribing chapter, which features the WHO pain ladder and drug formularies of paracetamol, non-steroidal anti-inflammatory drugs and opioid-based medications (http://www.fastbleep.com/medical-notes/other/21/50/525). This article therefore aims not to repeat the similar principles again 

             

            Possible sites of analgesia:

            Systemically:

            • Paracetamol – mechanism unclear
            • Non-steroidal anti-inflammatory drugs (e.g. ibuprofen) for cyclooxygenase (COX) inhibition and so reduce the formation of inflammatory mediators down the arachidonic acid cascade
            • Opioids for modulation and inhibition of pain transmission from the dorsal horn cells
            • *Serotonergic and tricyclics (e.g. sumatriptan, amitryptyline) for activation of the descending inhibitory pathways and in emotional stabilization
            • *Anticonvulsants (e.g. gabapentin) –mechanism unknown
            • *Noradrenergic agonist  (e.g. clonidine) for activation of the descending inhibitory pathways
            • *Calcium channel blocker (e.g. verapamil) for inhibition of the voltage-gated channels on the presynaptic membrane and the release of neurotransmitters.
            • *Medications that are commonly being used in the management of chronic or neuropathic pain

            Locally at or near the site of injury:

            • Local anaesthetic agents (e.g. lignocaine) to block the sodium channels needed for pain transduction and transmission. The possible routes of administration can range from topical cream, skin infiltration to various minor to major nerve-blockades (e.g. ring, intercostal, transverses abdominal plane blocks)

            Distally to the site of injury:

            • TENS (e.g. acutely during labour or in chronic pains) 
            • Regional nerve-blockades (e.g. brachial plexus, epidural, spinal blocks)
            • Neurosurgical interventions (e.g. cordotomy or some ablative procedures) as the last resort for the management of unresolved, severe chronic pain despite the above measures

             



            Complications of untreated acute pain:

            Multi-system manifestations:

            Neurological:

            • Presents as a "distracting pain" that masks other less painful but potentially more severe disease processes e.g. severe traumatic brain injury
            • Activation of the sympathetic nervous system

            Cardiovascular:

            • Hypertension, tachycardia
            • Increased vascular resistance due to vasoconstriction at the peripheries
            • Increased myocardial demand more than its supply, consequently, leads to ischaemia

            Respiratory:

            • Tachypnoea
            • Trauma to the thorax would result in poor compliance of the alveoli therefore put patient at riskof actelactasis, poor tidal volume and oxygenation (click here for a brief description of pulmonary compliance)
            • Poor cough and/ or poor clearance of sputum would increase the likelihood of chest infections e.g. pneumonia

            Gastrointestinal & Urinary:

            • Ileus and retention of urine

            Endocrine:

            • Acute stress response to trigger systemic release of cortisol, glucagon, renin, ADH, cytokines etc. The possible consequences could be hyperglycaemia, water retention, poor wound healing, impaired immune response and a negative nitrogen balance etc

            Immobility:

            • DVT/ PE 
            • Loss of muscle mass
            • Pressure sores

            LAST BUT NOT LEAST - CHRONIC PAIN!

            Summary

            This article explores the basic science behind the management of pain, with angle slightly inclined to acute pain. It is important for students to recall the 4 physiological mechanisms of pain, i.e. transduction, transmission, perception and modulation and to apply the knowledge to their actual clinical practice e.g. NSAIDs are used to reduce the soup of inflammatory mediators of pain and to relief sensitization; local anaesthetics are used to prevent formation of an action potential thereby dampen the transmission of pain etc. 

            Topic recommended to future reading would include opioid-related medical emergencies e.g. overdose, respiratory depression, urinary retention etc, the wind-up phenomenon of chronic pain and prescribing guidance for chronic pain, particularly in opioid conversion. There is also a merit to find out more about the surgical managements for difficult chronic pains. 

            Matthew Thakur has published an excellent article on the "neurobiology of pain". His article discusses the pathophysiology of pain in much more detail and can be accessed via: http://www.fastbleep.com/biology-notes/39/142/888

            References

            1. Anaesthesia UK. Physiology of pain. Accessed 2012 May. Available from: http://www.frca.co.uk/article.aspx?articleid=100591
            2. Anaesthetist.com. Pain physiology. Accessed 2012 May. Available from: http://www.anaesthetist.com/icu/pain/Findex.htm#pain3.htm
            3. Anaesthesia UK. Pain and neurotransmitters. Accessed 2012 May. Available from: http://www.frca.co.uk/article.aspx?articleid=100632
            4. Anaesthesia UK. Pain modulation. Accessed 2012 May. Available from: http://www.frca.co.uk/article.aspx?articleid=100119
            5. The University of Texas. Neuroscience online. Chapter 8: Pain modulation and mechanisms. Accessed 2012 May. Available from: http://neuroscience.uth.tmc.edu/s2/chapter08.html

             

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