Management of pain is very important in the clinical setting. A good assessment of pain is necessary to identify the type of pain and cause of the pain. It is a subjective experience and therefore there is a necessity of individualised pain management. Pain has an inter-relationship with the injury response and has physiological and psychological effects on the patient. These effects may lead to a poorer outcome in the patient therefore optimal pain management is important. Multi-modal pain management is effective and the pathophysiology of pain helps understand the use of different analgesic drugs.

Acute Pain and Chronic Pain

The International Association of the study of pain has defined pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’ (Merskey & Bogduk, 1994). Pain can be nociceptive pain or neuropathic pain. . Nociceptive pain could be somatic or visceral pain where somatic pain is usually described as a sharp, hot, stinging, well localised pain associated with local tenderness. Visceral pain is dull, cramping and colicky pain that is often poorly localised (Scott & McDonald, 2008). It is important to identify the cause of pain as it will help with effective individualised pain management. Neuropathic pain is ‘pain initiated or caused by a primary lesion or dysfunction in the nervous system’ (Loeser & Treede, 2008). These types of pain can be either acute or chronic pain. In the acute pain setting nociceptive pain is predominant but some patients may also present with neuropathic pain (Gray, 2008). Acute pain can be defined as ‘pain of recent onset and probable limited duration. It usually has an identifiable temporal and causal relationship to injury or disease’. Acute pain serves an important biological function. There is increasing evidence that recognizing acute pain early and effectively will delay or prevent the acute pain sliding into chronic pain or illness. In contrast to acute pain, chronic pain may serve no useful purpose. Chronic pain ‘commonly persists beyond the time of healing of an injury and frequently there may not be any clearly identifiable cause’ (Ready & Edwards, 1992). It possibly may cause extreme emotional, physical economic and social stresses upon the patient, the family and society.

Pathophysiology of pain

‘Nociception can be defined as the neural process that underlies the encoding and processing of noxious stimuli’ (Loeser & Treede, 2008). The somatosensory system is able to detect the stimuli that are noxious and potentially tissue-damaging and therefore, serves as an important protective mechanism. The somatosensory system involves multiple peripheral and central mechanisms which interact.

Pain is a subjective experience that is affected by psychological and environmental factors in each individual. The amount of pain that a particular stimulus creates depends on many factors other than the stimulus itself and therefore the sensation of pain is multifactorial (Eccleston, 2001).

Two major components can be distinguished in the pathological state of pain. They are the peripheral nociceptors that are activated by the noxious stimulus and the central mechanisms by which the afferent input generates a sensation of pain.

Peripheral nociceptors-

To detect a noxious stimulus the peripheral sensory organs (nociceptors) need to be activated and, transduced action potentials need to be conducted to the central nervous system. The nociceptive afferent nerve fibres are present throughout the body, including the skin, muscle, joints, viscera and meninges. Most of these afferent fibres are the non-myelinated slow conducting, small diameter, C fibres. Others are the myelinated, medium diameter Aδ fibres which conduct more rapidly. The C fibre afferents respond to mechanical, thermal and chemical stimuli. A variety of receptors such as the transient receptor potential vanilloid receptor 1 (TRPV1) (Patapoutian et al, 2009), acid- sensing ion channels (ASICs) and potassium channels respond to different noxious stimuli (Woolf & Ma, 2007). Endogenous modulators of the nociceptors include proteinases, pro-inflammatory cytokines, anti-inflammatory cytokines and chemokines. These may also act as signalling molecules in the pain pathway. Infection, inflammation or ischaemia causes tissue damage resulting in the release of local mediators by cell disruption, degranulation of mast cells or by the inflammatory cells which results in the direct activation of the nociceptors or sensitization of the nociceptors via ligand gated ion channels or metabatropic receptors.

Within the dorsal horn inhibitory modulation could also occur via non-nociceptive peripheral inputs, local inhibitory GABAergic and glycinergic interneurons, descending bulbospinal projections, and higher order brain function such as distraction and cognitive input. These inhibitory mechanisms exert their effect through neurotransmitters such as endorphins, enkephalins, noradrenaline and serotonin.

Pain relief can be achieved by either reducing the excitatory transmission by using agents such as local anaesthetics and ketamine or by enhancing the inhibition with agents such as opioids, clonidine and antidepressants.

Central Pathway-

There are two primary ascending nociceptive pathways present. The spinomescenphalic tracts that originate from deep in the dorsal horn and project to the medulla and brainstem and play an important role in integrating the nociceptive information together with arousal, homeostatic and autonomic responses. They also project to central areas which are concerned with discrimination of pain and also mediate the emotional component of pain. The spinobrachial pathway which originates from the superficial dorsal horn feeds areas with the brain that are involved with the affective and motivational component of pain.

Acute Pain and the injury response

Acute pain is one of the factors that mediates the activation of the complex neurohumoral and immune response to injury. The peripheral and central responses to injury in turn have a major impact on the mechanisms of acute pain. Thus there is an inter-relationship between acute pain and injury and if the injury response is prolonged there can be a negative effect on the outcome.

The response to noxious stimuli that occurs in injury or disease is a result of multiple interactions between different neural systems and psychological factors. The interactions of the sensory, motivational and cognitive processes act on the motor systems and produce the complex physiological behaviour, and affective responses which characterize acute pain.

Generally the immediate response involves:

An involuntary response that involves the segmental and suprasegmental reflex response that helps to usually preserve homeostasis which is manifested by the –

Contraction or spasm of the skeletal muscles

Increased glandular, vasomotor and sudomotor activity

Changes in the cardiovascular and respiratory systems, alterations in the visceral functions and a widespread and general endocrine response.

A cerebral cortical response which includes the emotional experience of pain, psychodynamic responses which produce affective responses such as anxiety, apprehension and general responses which are characteristic of acute pain.

The immediate response will also involve the release of local mediators which will result in biochemical and metabolic changes that will decrease the threshold of the nociceptors and cause local tenderness and hyperalgesia.

Pain is finally an emotional response which requires consciousness. During general anaesthesia the patient who reacts to the surgical incisions made by moving, by an increase in blood pressure and heart rate, or altering the respiratory pattern is not feeling the pain but is producing reflexes to the noxious stimuli. Some reflex responses to noxious stimuli (intense stimulation of the mesentery) can be only be suppressed by general anaesthesia. Muscle relaxants are able to suppress the reflex muscle movements but are unable to suppress the circulatory, respiratory and endocrine response to injury. Regional anaesthesia is able to suppress these reflex responses by disrupting the afferent and efferent limbs of these reflexes.

Systematic effects of pain

Experiments have shown that pain in the absence of injury is associated with a hormonal/metabolic response which included increased levels of cortisol, catecholamines and glucagon and also a decrease in sensitivity to insulin (Greisen et al, 2001). It is believed that there is a correlation between the magnitude of pain caused by tissue injury and the activation of the sympathetic systems which includes the activation of the cardiomotor neurones, vasoconstrictor neurones which innervate the resistance vessels, sudomotor neurones and sympathetic pre ganglionic neurons that innervate the adrenal medulla. As a result of this activation of the sympathetic system there is an increase in the heart rate, arterial blood pressure, cutaneous conductance, and levels of plasma norepinephrine or epinephrine. This assumption was derived by the fact that experiments have shown that graded noxious stimuli shows a graded activation of the different functional sympathetic neurons.

The activation of the sympathetic efferent nervous systmen by pain and the subsequent increase in heart rate, inotropy and blood pressure increases the myocardial oxygen demand. There is also a reduction in the myocardial oxygen supply. This increases the risk in cardiac ischaemia especially in patients with pre-existing cardiac disease.

The enhanced sympathetic activity also affects the gastrointestinal system and results in reducd gastrointestinal motility which contributes to post-operative ileus. The widespread effect on the gut and urinary tract motility may lead to post operative ileus, nausea, vomiting and urinary retention.

Severe pain that is present after upper abdominal and thoracic surgery may contribute widespread changes in pulmonary function, and increase in abdominal muscle tone and an associated decrease in diaphragmatic function. This may result in an inability to cough and clear lung secretions which may lead to lung atelectasis and pneumonia. A reduction in functional residual capacity may result in ventilation-perfusion abnormalities and hypoxaemia.

The response to injury also suppresses the cellular and humoral immune function and contributes to a hypercoagulable state following surgery. Prolonged pain can reduce physical activity and lead to venous stasis and increased risk of deep vein thrombosis and consequent pulmonary embolism.

Acute pain after surgery, as mentioned above, is said to be an activator of the sympathetic stress response but a recent study done by Ledowski et al., has shown that in contrast to common belief the severity of postoperative pain does not appear to have an association with the degree of sympathetic stress response after surgery. The mean arterial pressure, heart rate, respiration rate, plasma levels of epinephrine and norepinephrine were measured and they showed no relation with the rate of pain. It was therefore importantly stated that the absence of sympathetic stimulation does not guarantee that there is no pain (Ledowski et al., 2012).

Importance of Acute Pain management

Patients at a higher risk of complications from unrelieved acute pain include very young or elderly patients, patients with co morbidities and those who are undergoing major surgery (Liu & Wu, 2008).

Effective acute pain relief is of great importance to anyone who is treating patients undergoing surgery. Pain relief should be achieved especially for humanitarian reasons and for the comfort of patient but as pain has a physiological effect pain relief has been shown to have a significant physiological effect. Effective pain relief means enhanced recovery which means patients recover from surgery more swiftly and results in earlier discharge from hospital. Patients are able to resume their normal daily lifestyle more quickly and there is also reduction in the onset of chronic pain syndromes (Fawcett et al., 2012).

If acute pain is not relieved it can affect the patient psychologically as well. It may result in increased anxiety, inability to sleep, demoralisation, loss of control and feeling of hopelessness (Cousins et al., 2004).

The goal of pain management is to reduce or eliminate the pain and discomfort and must take into account the needs of the patient. The ultimate determinant of adequate pain relief will be the patient’s perception of pain.

Multimodal management of pain

The responsibility for recognizing and managing acute pain lies within the entire healthcare team. The acute pain team provides leadership, education and forward planning as well as assistance with the management of more complex problems. The responsibility for managing more straightforward pain cases would lie primarily with the doctors and nurses on the ward.

Patients at risk of more severe acute pain are patients with pre-existing chronic pain, those taking strong opioid analgesics, those with high levels of anxiety and who have had a previous poor pain experience.

The world health organization has introduced the concept of the analgesic ladder (Figure 1) in which paracetamol is used with or without non steroidal anti inflammatory drugs (NSAIDs) initially, then weaker opioids such as codeine and then strong opioids such as morphine are used. This model is perfect for conditions in which the pain intensity gradually increases over time but may not be very appropriate for conditions in which the acute pain is expected to decrease over a short period of time. In such situations the inverse of this approach could be used where a number of different drugs are used initially and the more potent analgesics which usually have more side effects are tapered off and discontinued as the intensity of the pain decreases (Vickers 2010).

Figure 1: The WHO analgesic ladder

Analgesics can be divided into three main groups. Paracetamol, the NSAIDs and Cyclo-oxygenase (COX) 2 inhibitors (‘Coxibs’), and the opioids. The term opioids include the naturally acting opioids such as morphine, the synthetic opioids such as fentanyl as well as the endogenous opioids such as the endomorphins. The concept of multi-modal analgesia is used in which a combination of drugs that have a different mechanism of action can be used to maximize the pain control with minimum amount of side effects. The combination of tramadol and paracetamol synergistically act together to give a greater effect. (Figure 2)

Figure 2: The efficacy of different analgesic alone and in combination with other analgesics

Paracetamol which is an anti pyretic and analgesic drug has no anti-inflammatory actions. It is known to act via the central nervous system and has effects on COX pathways, stimulates descending inhibitory pathways via serotonin and inhibits substance P. Paracetamol is usually prescribed either alone or in combination to all patients who have no contraindications and have post operative pain.

NSAIDs act via inhibiting the cyclo-oxygenase enzyme which catalyses the conversion of arachidonic acid to prostaglandins. Their potent analgesic and anti-inflammatory effects as well as their relatively common adverse effects are due to this action. The NSAIDs that are most commonly used for post-operative pain in the UK are ibuprofen and diclofenac.

NSAIDs have a number of side effects which include inhibition of platelet aggregation, interaction with other anticoagulants, peptic ulceration and bleeding, exacerbation of asthma and renal impairment. The inhibition of platelet aggregation results in a prolonged bleeding time but do not affect the prothrombin time or the activated partial thromboplastin time.

The effect on platelet function may complicate other anticoagulants such as warfarin or heparin. NSAIDs are able to displace warfarin bound to plasma proteins further inhibiting coagulation therefore NSAIDs are prescribed with caution to patients receiving other anticoagulants. NSAIDs are avoided in patients with peptic ulcers or a past history of peptic ulcer bleeding. Approximately 5% of asthmatic patients exhibit aspirin-induced asthma and there maybe some cross-reactivity with NSAIDs therefore they are used with caution in asthmatics who have not been prescribed NSAIDs before. Prostaglandins play role in maintaining the blood flow to the kidneys and therefore NSAIDs in healthy patients may temporarily affect kidney function. NSAIDs should be avoided or prescribed cautiously in patients who have kidney dysfunction or are at risk of developing kidney dysfunction (Vickers 2010).

The cyclo-oxygenase exists in two forms namely, COX1 and COX2. The constitutive form of the enzyme is COX1 which maintains the normal functions of prostaglandins such as platelet aggregation, protection of the gastric mucosa and perfusion of the kidneys. The inducible form which is COX2 is triggered by stimuli such as tissue injury and is responsible for the inflammation and pain caused by prostaglandins. Selective inhibitors of COX2 were discovered and were not shown to have the side effects associated with the COX inhibitors but it was revealed that they have an increased risk of myocardial infarction or stroke in high risk patients.

Codeine is the most commonly used weak opioid. Since codeine is a prodrug of morphine and needs to be converted into the active analgesic in the gut in a proportion of the population codeine may have little or no analgesic effect. Tramadol, although regarded as an opioid analgesic has only a weak effect on the mu opioid receptors and therefore less respiratory depression than seen with morphine. Tramadol has an inhibitory effect on the re-uptake of both noradrenaline and seronin therefore is more effective in neuropathic pain when compared to pure opioids. Nausea, vomiting dizziness and drowsiness are common side effects seen with Tramadol.

Strong opioids are used to manage severe pain and morphine is usually the first choice for the majority of patients. Side effects of opioids include sedation, nausea, vomiting and constipation. A serious side effect of opioids is respiratory depression and the combination of respiratory depression and increasing level of sedation acts as a warning sign. Morphine can be administered intermittently as a part of the multimodal management of pain. Patient controlled analgesia (PCA) has often been shown to have better pain relief than the intramuscular delivery of opioids.

Adjuncts to these major classes of analgesic drugs may be local anaesthetics, ketamine and gabapentinoids.

Conclusion

The effect of analgesic drugs vary greatly from patient to patient and the response cannot be predicted. Studies have shown that the health care team which includes doctors and nurses overestimate the length of action of the drug and the strength of the drug, and have concerns over side effects, in the case of opioids vomiting, sedation and dependency, therefore under-treating acute pain especially in the post-operative setting. Improvement can be achieved by better education for all staff concerned with the delivery of postoperative pain relief and by making the assessment and recording of pain levels part of the routine management of each patient.