• Despite the importance of pain in clinical practice this is not a major topic that regularly appears in the exam. That said trainees need to have a basic idea of the modes of action of the various classes of pain medication used in orthopaedic practice along with principles of pain management.
• It is important to have a reasonable working knowledge of pain so as to have something to say if the topic appears in the viva exams.

• An unpleasant sensory and emotional experience associated with actual or potential tissue damage (International Association of the Study of Pain).

• Definition: Noxious stimuli: stimulus, which is damaging to normal tissues. 
• Definition: Nociceptor: a receptor preferentially sensitive to a noxious stimulus or to a stimulus, which would become noxious if prolonged. 

Nociceptor types

• Peripheral activation of nociceptors is modulated by a number of chemical substances, which are produced and released when there is cellular damage (e.g. potassium, serotonin, bradykinin, histamine, prostogladins, leukotrienes and substance P).
• These substances influence the degree of nerve activity and intensity of the pain sensation. 

• The release of substance P and histamine induce vasodilation locally around the injured tissue.
• In turn this lead to behaviour that keeps the area away from noxious stimuli.

Hypersensitivity

• Repeated stimulation can lead to sensitisation of the peripheral nerve fibres, lowering pain thresholds and leading to spontaneous pain, e.g. sunburn leading to cutaneous hypersensitivity. 
• Hypersensitivity can be diagnosed through history and examination. Hypersentivity can be divided into four main conditions:

1. Allodynia: Pain due to a stimulus that normally would not provoke pain.
2. Dysaesthesia: An unpleasant abnormal sensation.
3. Hyperalgesia: An increase response to a stimulus that is normally painful. 
4. Hyperesthesia: Increased sensitivity to stimulation. 

Pain pathways

• Central pathways (spinothalamic and trigeminal pathways):
• Transmission of pain and normal temperature (<45°C) from the body to the brain. 
• Visceral organs only have C fibre nociceptors and therefore no reflex action due to visceral organ pain. 
• Spinothalamic pathway:
• The nerve fibres from the dorsal root ganglia enter the dorsal root and send branches one to two segments up and down the spinal cord (dorsolateral tract of Lissauer). 
• Nerve fibres enter the grey matter making connections with rexed lamina. 
• Aδ fibres innervate cells within the marginal zone (rexed lamina I) and C fibres innervate cells within the substantia gelantinosa (rexed lamina II).
• These nerve cells then innervate cells within the nucleus proprius (rexed lamini IV, V, VI) and send nerve fibres across the midline to ascend via the anterolateral tract (white matter).
• These fibres travel through the medulla and pons and innervate cells within the thalamus. 
• Dysfunctions in the thalamic pathway may themselves be a source of pain, e.g. stroke patients with central pain in the area of paralysis. 

Figure 1: Spinothalamic Pathway

Figure 2: Axial section of spinal cord (Rexed lamina labeled)

Trigeminal pathway

• Noxious stimuli to the face are transmitted in the nerve fibres originating from the nerve cells in the trigeminal ganglion and cranial nuclei (VII, IX, X).
• The nerve fibres enter the brainstem and descend to the medulla and innervate a subdivision of the trigeminal nuclear complex.
• The fibres then cross the neural midline and ascend to innervate the contralateral thalamic nerve cells. 
• Nerve fibres of normal sensation (light touch and pressure) also innervate cells of the thalamus in the same area as the spinothalamic and trigeminal pathways. 
• From here thalamic nerve fibres communicate with the cortical areas of the brain. 
• By having the somatic and nociceptive information connect with the same cortical area info on the location and intensity of the pain can be processed to become a localised painful feeling.

Figure 3. Trigeminal Nerve pathway

• Endogenous mechanism of pain modulation is thought to provide the advantage of increased survival in all species. 
• Three mechanisms:

1. Segmental inhibition system (gate theory)
2. Opioid system 
3. Descending inhibitory system 

• Segmental inhibition (gate theory – Melzak and Wall, 1965)¹.
• Synapse between nociceptors fibres (Aδ/C) and dorsal root ganglia can be diminished or blocked by an inhibitory neuron within the spinal cord. 
• The inhibitory neuron is activated by Aβ fibres (light touch, large diameter). 
• Therefore stimulation of light touch fibres can block the pain transmission at the nociceptor – dorsal root ganglia synapse. 
• The development of transcutaneous electrical nerve stimulation (TENS) was the result and is an explanation of why rubbing the injured area reduces the pain sensation.

Figure 4.Gate control theory

• Without any stimulation, both large and small nerve fibres are quiet and the inhibitory interneuron (I) blocks the signal in the projection neuron (P) that connects to the brain. The “gate is closed” and therefore NO PAIN.
• With non-painful stimulation, large nerve fibres are activated primarily. This activates the projection neuron (P), BUT it ALSO activates the inhibitory interneuron (I), which then BLOCKS the signal in the projection neuron (P) that connects to the brain. The “gate is closed” and therefore NO PAIN. 
• With pain stimulation, small nerve fibres become active. They activate the projection neurons (P) and BLOCK the inhibitory interneuron (I). As activity of the inhibitory interneuron is blocked, it CANNOT block the output of the projection neuron that connects with the brain. The “gate is open”, therefore, PAIN!!

Figure 5. Gate theory of pain

I = "Inhibitory Interneuron"; P = "Projection Neuron"

- = inhibition (blocking); + = excitation (activation)

• Opioid system
• Opioid derivatives are powerful analgesics (morphine, diamorphine, codeine). 
• Opioid receptors are present in the spinal cord, periaqueductal grey matter and the ventral medulla. Three types μ(mu), δ(delta), κ(kappa). 
• Enkephalins, endorphins and dynorphin are naturally occurring peptide ligands that bind to opioid receptors. 
• The peptides modulate nociceptive input in two ways: 

1. Block neurotransmitter release by inhibiting calcium influx in the pre-synaptic terminal. 
2. Open potassium channels, which hyperpolarise neurons inhibiting excitatory action potentials. 

• Systemically administered opioid analgesics can bind to the opioid receptors and modulate pain transmission.

• Descending inhibitory system (adrenergic and serotoninergic):
• From the periaqueductal grey matter and the rostral medulla descending nerve fibres can modulate the ascent of nociceptor information at the dorsal root ganglia. 
• Noradrenaline and serotonin are the main neurotransmitters in this pathway. 

• C fibres convey pain from visceral organs. They converge in the same area where somatic peripheral nerves converge in the substantia gelatinosa of the spinal cord grey matter. 
• Therefore the brain localises the pain sensation as if it were originating from the somatic peripheral area rather than the organ itself, e.g. right shoulder tip pain in cholecystitis.

• Defined by the International Association for the Study of Pain: Consists of continuous pain (allodynia or hyperalgesia) in part of an extremity after trauma. 
• CRPS is associated with sensory, motor, autonomic, skin and bone abnormalities in a limb.²Occurs after trauma but there is no relation with severity of trauma, 10% after minor trauma. 
• Diagnosis based on clinical history and examinations. Investigations can be used as adjuncts. 
• Budapest criteria³specificity 0.69.
• All following statements must be met: 
• The patient has continuing pain that is disproportionate to any inciting event. 
• The patient has at least one sign in two or more categories below.
• The patient reports at least one symptom in three or more categories below. 
• No other diagnosis can better explain the signs or symptoms.

• CRPS type 1: absence of nerve lesion. 
• CRPS type 2 (causalgia): presence of nerve lesion.
• Warm CRPS: 70% prevalence. 
• Cold CRPS: 30% prevalence (worse prognosis). 

Imaging 

• Radiographs: osteopenia (insensitive) useful if both hands imaged for comparison. 
• Bone scan (three phase): Increased radiotracer uptake in mineralisation phase in joints that are not affected by the initial trauma.⁴

Pathophysiology 

Prevention 

• Vitamin C (200 mg/500 mg/1500 mg for 50 days reduced incidence of CRPS in a high quality trial in patients after wrist fractures.⁵

Treatment 

• Physical therapy 
• Pharmacological therapy 
• Nerve stimulation 
• Regional nerve blocks 
• Chemical sympathectomy 
• Surgical sympathectomy (Cossins systematic review).²
• Strong evidence: rehabilitation and physiotherapy can reduce pain and improve function. Oral/IV bisphosphonate therapy.
• Moderate evidence: low dose IV ketamine (long-standing CRPS).

• The WHO pain ladder was originally introduced as a framework for treating cancer pain in 1986 with modifications in 1997.
• Treatment of pain should begin with a non-opioid medication. If the pain is not properly controlled, one should then introduce a weak opioid. If the use of this medication is insufficient to treat the pain, one can begin a more powerful opioid. One should never use two products belonging to the same category simultaneously. The analgesic ladder also includes the possibility of adding adjuvant treatments for neuropathic pain or for symptoms associated with cancer.
• The WHO guidelines can be used for all patients with either acute or chronic pain who require analgesia.
• Although there has been a number of criticisms due in part to omissions, developments of new techniques and medications the WHO treatment guidelines are still considered a valid tool to use.

• A stepwise ladder is used:

1. Non-opioid analgesic/basic analgesia paracetamol 1 g QDS
2. Tricyclic antidepressant (TCA) amitriptyline
3. Anticonvulsant gabapentin. If TCA contraindicated or lancinating pain (electric shock or stabbing)
4. Tramadol
5. Secondary pain care referral

• A patient’s pain perceptions, coping strategies, mood changes, disturbed sleep and anxiety may also need to be addressed. 
• Treating any associated anxiety or depression may reduce the requirement for analgesics.

Pain must be assessed using a multidimensional approach, with determination of the following:

• Chronicity
• Severity
• Quality
• Contributing/associated factors
• Location/distribution 
• Aetiology of pain, if identifiable
• Mechanism of injury, if applicable
• Barriers to pain assessment
• Pain scales can be useful:

Single dimensional scale:

• Measures a single dimension of pain, usually pain intensity. Useful in acute pain when aetiology is clear.

Multidimensional scales:

• These measure the intensity, nature and location of pain, and in some cases, the impact that pain is having on a patient’s activity or mood. Useful in complex or persistent acute or chronic pain.

Non-opioid analgesics

Opioid analgesics

Mode of action

• Opioid peptides bind to opioid receptors (mu, delta and kappa).
• Opioid drugs act on the central and peripheral nervous system. 
• Routes of administration: oral, intravenous, subcutaneous, epidural.
• Analgesic effects are a result of opioid agonists binding to opioid receptors leading to reduced neuronal excitability and inhibition of neurotransmitter release. 
• Naloxone is used to reverse the effects of opioid agonists and inhibits all three opioid receptors, but has the highest affinity to mu receptors. 

Strong opiates

• Morphine – has a high affinity to mu receptors and has significant first-pass metabolism (i.e. the fraction reaching the systemic circulation is much less than that absorbed via oral administration). Available in long acting and modified release forms (i.e. oxycodone, morphine-sulphate).
• Diamorphine – is metabolised to morphine and is more lipid soluble than morphine, which is an advantage when used for subcutaneous infusion. 
• Pethidine – synthetic substance that has a rapid onset and is more sedative than morphine. 
• Fentanyl – highly potent with a short half-life (1–2 hours). Commonly used in severe acute pain or during anaesthesia. 

Weak opiates 

• Codeine – demylinated in the liver to morphine. Has a lower efficacy than morphine. 
• Tramadol – centrally acting analgesic with a low affinity to opioid receptors. Also produces analgesia by its inhibitory actions on 5-HT and noradrenaline reuptake. Metabolised in the liver via the cytochrome P450 pathway to five active metabolites. It is excreted by the kidneys and may accumulate in renal impairment. 

Effects

• Induces analgesia, euphoria, respiratory depression, nausea/vomiting, constipation, pupillary constriction, histamine release (leading to bronchospasm and pruritis).

Patient-controlled analgesia (PCA)

• PCA is commonly used in the postoperative setting with opiate analgesics administered intravenously or subcutaneously. The system allows the patient to administer small boluses of drug in response to their pain requirements, usually complemented with a continuous background infusion. The aim is provide a constant plasma level of drug. Overdose is avoided by limiting the size of the bolus dose, total dose given and using a lock-out interval. Drugs with short half-lives are favoured and regular anti-emetics must be given to prevent nausea and vomiting. 

• Many of the advancements in surgery and outcomes have only been possible due to the advances in anaesthesia and critical care.

The phases of an anaesthetic can be subdivided into the following:

• Preoperative visit, planning and pre-medication
• Induction of anaesthesia and airway control
• Maintenance of anaesthesia.
• Emergence from anaesthesia
• Postoperative recovery

• General anaesthesia encompasses the triad of analgesia, anaesthesia and muscle relaxation. Rather than using a large dose of a single drug to establish the clinical triad, a combination of drugs is used in smaller doses, thus avoiding dose-related adverse effects, and is termed “balance anaesthesia.”
• Intravenous and inhalation induction agents, and muscle relaxants will be summarised in the tables below. 

Intravenous induction agents 

CO = cardiac output

SVR = systemic vascular resistance

LMA = laryngeal mask airway

HR = heart rate 

BP = blood pressure

NMDA = N-methyl-d-aspartate receptor

Inhalation agents

Muscle relaxants

• Muscle relaxants are used to facilitate tracheal intubation and provide optimal operating conditions. Muscle relaxants target the neuromuscular junction (NMJ). At the end of the procedure muscle relaxants can be rapidly reversed with the use of neostigmine, which has a plasma half-life of 60 minutes, longer than all the commonly used muscle relaxants. Neostigmine is an antagonist to acetylcholine (ACH) esterase (the enzyme that breaks down ACH) resulting in a flux of ACH at the NMJ.
• A list of commonly used muscle relaxants with their benefits and side effects are shown below: 

NMJ = neuromuscular junction 

ACH = acetylcholine

• Adjuncts to anaesthesia include anti-emetics, which aim to reduce the incidence of postoperative nausea and vomiting. Local anaesthetic and peripheral blocks used in conjunction with general anaesthesia have led to improved postoperative pain relief and aided postoperative physiotherapy.

• Regional anaesthesia involves infiltration of local anaesthetic to block sensory and motor nerves. Regional anaesthesia makes the operative site insensate and provides peri and postoperative pain relief. The duration of motor and sensory blockade depends on the type and concentration of local anaesthetic agents and whether any additive agents are used. 
• Types of regional anaesthesia used in orthopaedic surgery are listed in the table below: 

• Cocaine was the first anaesthetic to be discovered and is the only naturally occurring one, indigenous to South America and the West Indies. All other local anaesthetics are synthetically derived from cocaine. Procaine was synthesised in 1904 and lignocaine in 1943. 
• All local anaesthetics produce their effects by blocking sodium-gated voltage channels, which prevents depolarisation of the nerve cell and propagation of the action potential down the nerve.
• The duration of action of the drug is dependent on protein binding and its clearance from the injection site.
• Protein binding for the longer acting agents, i.e. bupivacaine and ropivicaine, is 95%; this is compared to 65% for lidocaine a shorter acting drug. The clearance from the injection site is dependent on local blood flow. Short acting agents, i.e. lignocaine, cause vasodilation thus potentiating clearance. Vasopressors, i.e. adrenaline, can be added in order to prolong the duration of action. Interestingly, local blood flow has little influence on the longer acting agents due to their high percentage of protein binding, therefore the addition of vasopressors does not prolong their duration of action.

Commonly used local anaesthetics and their classes

• Local anaesthetics can be split depending on their chemical composition, i.e. amides and esthers. Amides are now more commonly used, i.e. lidocaine, prilocaine, bupivacaine, levo-bupivacaine, ropivacaine. Esthers, e.g. cocaine, chlorprocaine and benzocaine, are now rarely used. In the table below you can see listed the most commonly used local anaesthetics with their maximum doses and duration of onset and action.

• Local anaesthetics are alkaline and this allows them to cross the lipid cell membrane. In an acidic environment, i.e. abscess, the local anaesthetic is unable to penetrate the cell membrane and therefore is ineffective. 

Complications

• Commonly associated with errors of dose or intravenous administration. The complications are related to membrane destabilisation of cells.
• Neurological – perioral and glossitic parasethesia, dizziness, drowsiness, tinnitus, seizures. 
• Cardiovascular – bradycardia, hypotension, cardiac arrhythmias, i.e. ventricular fibrillation and asystole. 
• Neurological effects are usually witnessed first followed by cardiovascular collapse. Management is supportive. A definitive airway should be established, ensuring adequate oxygenation and ventilation. Benzodiazapines and phenytoin can be used to control seizures. Cardiac monitoring is mandatory, as arrhythmias require urgent treatment. 
• The addition of adrenaline to local anaesthetics should not be used on tissues with end arteries, i.e. digit and penis, as the induced vasoconstriction may result in tissue ischaemia. Caution should be used when infiltrating around skin flaps for the same reason.
• Subcutaneous infiltration of a large dose of local anaesthetic around the operative site is now commonplace in lower limb arthroplasty. Despite initial concerns over toxicity, this technique has been shown to be safe and aid postoperative recovery, Adrenaline is added to prolong duration of action and NSAIDs to add to the local analgesia.

• Encompasses epidural and spinal anaesthesia.
• Epidural anaesthesia (a catheter placed in the epidural space and allows for continuous top up).
• Spinal anaesthesia (local anaesthetic infiltrated in the subarachnoid space).

Epidural anaesthesia

• Epidural anaesthesia was once commonplace following lower limb arthroplasty surgery. Although epidural catheter placement produces excellent postoperative analgesia, the motor block will also persist, therefore delaying a patient’s early rehabilitation. Epidurals are now only rarely used in orthopaedic surgery, mainly due to the advancements in spinal anaesthesis which will be the focus of this section.

Spinal anaesthesia

• First performed by Bier in 1899. Principles have remained the same. A needle is passed into the subdural space and a single shot of local anaesthetic is infiltrated, bathing the spinal nerve roots. Spinal anaesthesia has the bonus of providing postoperative pain relief. The duration of the block is dependent on the volume of local anaesthetic used. The sympathetic block is higher than the motor and sensory block.
• Postoperative anaesthesia can be prolonged with the addition of opiates. The addition of an opiate to the local anaesthetic can prolong the analgesic effect for up to 24 hours without prolonging the motor block; therefore, enabling early active rehabilitation.
• Side effects include pruritis and more seriously respiratory depression, and risk can be reduced by using lipophilic short acting opiates, i.e. fentanyl rather than morphine. Clonidine, a selective α2 agonist, can be used instead of opiates, to enhance analgesia with sparing of motor and proprioception fibres. Side effects include sedation, bradycardia and hypotension.
• 0.5% Hyperbaric bupivocaine is the most commonly used local anaesthetic agent. In general, hyperbaric agents are used in order to provide a more predictable level of block. Baricity is a term used to describe the density of a solution in comparison to cerebrospinal fluid (CSF).
• Hypobaric preparations are far less predictable; however, do offer a benefit in providing unilateral anaesthesia to the non-dependent limb, i.e. patients with a fractured neck of femur. The height of the block can be controlled by patient positioning within the first 10 minutes following infiltration, i.e. tilting the table head down or placing the patient in the lateral decubitus position. A rapid onset of block within 3–5 minutes is the norm. Maximal effects may take up to 20–30 minutes.

Contraindications 

Complications 

• Postdural tap headache had a higher incidence in obstetric CNA block. It is caused by an increased CSF leak which is related to large needle gauge. Research into producing a more atraumatic needle design has been successful in reducing this complication. The standard beveled cutting needle (Quincke) has now been replaced with the blunter pointed needle (Sprotte).

Technique

• Resuscitation facilities and preparation for general anaesthesia must be available. IV access is mandatory prior to starting the procedure.
• A spinal anaesthetic can be administered with the patient sitting or lying on their side. The interveterbral space can be increased by increasing lumbar flexion. An aseptic technique is adopted. The spinal cord terminates at the level of L1 in adults (L3 infants). The subarachnoid space terminates at S2. The L3/L4 intervertebral space is the most commonly used space and can be identified using Tuffier’s line (a line adjoining the superior border of both iliac crests). L2/L3 and L4/L5 spaces can be identified using palpation.

• This complication requires attention. It occurs due to a continued increase in the level of block until it affects the cervical cord and brainstem, and as a result leads to respiratory, cardiovascular and neurological collapse. 
• Symptoms usually begin within minutes but may take up to 30 minutes. Nausea and a sensory level higher than T1 are early signs and should be acted upon. Risk factors include prior epidural (recent top-up), large anaesthetic dose, raised intra-abdominal pressure and immediate supine position.
• (http://www.frca.co.uk/Documents/180%20Complete%20spinal%20block%20after%20spinal%20anaesthesia.pdf).

Figure 9. Quincke needle pic 

Figure 10. Sprotte spinal needle 

• There are too many nerve blocks to discuss in detail; the type and surgery location are displayed in the earlier table. 
• The efficacy of the block is related to the experience of the operator. A detailed knowledge of standard and aberrant anatomy is required for success. Ultrasound and nerve stimulators are used to improve the accuracy of needle placement, with the aim of placing the needle in the same tissue plane as the targeted nerve.
• Complications include local haemorrhage, neuropraxia and permanent axontemesis (rare incidence of 1 in 10,000). Axontemesis is caused by intra-fascicular nerve injection leading to ichaemia. It can be reduced by avoiding direct contact of the nerve, performing the block with the patient awake and not injecting if the patient is feeling pain and to infiltrate under low pressure. 
• Peripheral blocks have been shown to aid postoperative analgesia and improve outcomes in recovery.⁶

• Chemical thromboprophylaxis is now the gold standard for lower limb arthroplasty. A range of various anticoagulants is now available, i.e. low molecular weight heparin, dabigatran, rivoroxaban and apixoban.
• The European Society of Anaesthesiology has published guidelines on the timing of postoperative administration and the safe time interval between the last dose and central neuraxial block administration.⁷