Postoperative pain (POP) is considered the most typical form of acute pain.
Acute pain is the brief and intense pain that is generally cause and time related with tissue damage.
It is the epiphenomenon of neurovegetative, psychological and behavioural responses that lead to an unpleasant sensorial and emotional experience. In the past pain therapy was practiced occasionally and approximately as most medical and nursing staff and some patients too considered pain an unavoidable component of normal postoperative progress.
Recent years have marked a growing interest in the prevention and treatment of this syndrome.
In fact, progress in the physiopathology of pain and the pharmacology of analgesics, the development of innovative and sophisticated antalgic methods, the demonstration of complications related with pain symptoms and greater attention paid to patients’ quality of life have contributed to spread the culture of “pain therapy” and to make the problem known under its scientific aspects.
Despite this, today a considerable part of patients undergoing surgery continues to experience avoidable suffering: a recent re-examination of scientific literature reports an incidence of moderate to severe pain in 25-50% of patients who undergo major surgery (thoracic, abdominal and orthopaedic) and moderate pain in more than 25% of surgery outpatients. The international scientific community basically agrees on the need to implement guidelines to treat postoperative pain.
The SIAARTI [Italian Society for Anaesthetics Analgesia Resuscitation and Intensive Care) has processed some warnings on this issue, starting from the premise that postoperative pain control should become part of a treatment plan for the “postoperative disease”.
This plan should consider pain the “fifth vital parameter” to be monitored along with heart rate, arterial pressure, diuresis and body temperature.

PHYSIOPATHOLOGY OF ACUTE POSTOPERATIVE PAIN

Sensitivity to pain is developed by a complex anatomical system comprising peripheral receptors also called nociceptors that transduce painful stimuli, special transmission routes, supraxial centres, which process algic inputs that start along peripheral areas and descending routes by modulating and controlling pain-related information.
Surgery’s attack on tissue activates the nociceptors present in the skin, muscles and viscera.
Nociceptors are free endings of type A´ afferent fibres (myelinic fibre gauged below 3¼ and a conduction speed of 12-30 m/s) and type C (amyelinic fibre with a 1¼ diameter and a conduction speed of 0.5-2 m/s), whose cell body is in ganglia connected to the spinal cord’s posterior root.
These ganglia (first level neurons) send their terminal axons to second level neurons located in the posterior horns. These neurons’ terminal axons form the lateral spinothalamic tract and synapses in the thalamus with third level neurons.
These later originate fibers directed towards the somatosensory cortex. In these terms nociceptors and ascending sensitive routes would be considered an articulate system organized to receive and transmit the stimulus of pain. In practice, progress made by research has revealed neurophysiological and neurochemical events that control a greater functional complexity. In fact, there are both peripheral and central sensitisation events that cause hyperalgesia, which is an alteration of sensitivity that greatly emphasizes the intensity of pain. Nociceptors are sensitised by chemical mediators that have an inflammatory and vasoactive action (potassium, bradikynins, prostaglandins) and are released by the cells and vascular endothelium in response to tissue damage. These substances lower receptor excitement threshold and increase the discharge frequency of afferent peripheral fibres, causing primary hyperalgesia.
The increased excitability of small fibres results in a greater presynaptic release of neurotransmitters such as glutamate, substance P and neurokinins.
These neurotransmitters act both peripherally and spinally, amplifying the response to pain. Substance P produces vasodilation that results from a further release of bradykinin and mastcell degranulation, which releases histamine and serotonin. These autacoids activate primary afferent nerves, sensitise nociceptors near lesion sites and enlarge the field of peripheral reception. This establishes a vicious circle that on the one hand contributes to maintain primary hyperalgesia and on the other extends hyperalgesia to the lesion’s neighbouring areas, generating secondary hyperalgesia. Axially the interaction between neurotransmitters and receptors present on spinal neurone membranes causes the appearance of slow post-synaptic potentials. As the activity of afferent peripheral fibre gradually increases the release of neurotransmitters, we notice a growing post-synaptic depolarization (neuronal wind up).
The persistence of these events produces permanent functional modifications in dorsal horn neurones. These changes are clinically translated in prolonged hyperalgesia and allodynia, pain caused by stimuli that are normally not painful (fig.1).
Besides the ascending route, the system in charge of the nociception also comprises descending routes that control pain. At least two groups of fibres play a decisive role in the inhibiting modulation of pain: the opioid system and the noradrenergic system. Receptors for endogenous opioids (encephalines and ²-endorphines) and for amines (noradrenaline, serotonin) are variously distributed in the CNS both spinally and supraspinally, especially in the grey matter around the brain acqueduct, in the reticular formation and in the raphe nucleus.
Opioid and noradrenergic neurotransmitters share the same method of action on first level neurone presynaptic membranes: the agonist and receptor interaction hyperpolarizes afferent fibres preventing the propagation of the painful stimulus and the release of glutamate, substance P and neurokinin exciting neurotransmitters.
Besides it seems that endogenous opioids intervene in pain modulation even with post-synaptic inhibition mechanisms. Exogenous opioids and recently ±2 agonist drugs have an analgesic action as they interact with the central and spinal receptors that are naturally involved in the inhibiting modulation of pain.
From what has been described it is obvious that the knowledge of acute post-operative pain’s physiopathology is the premise for the rational use of analgesic drugs that have different methods of action and for the choice between the method and time of administration that can be applied.

ACUTE PAIN ITS SYSTEMIC EFFECTS

Besides, from a typically ethical viewpoint adequate post-operative analgesia is important against the harmful effects pain exercises on various organs and systems.
Tissue lesion causes important physiopathological alterations typical of the “stress reaction” that can be put down to reflex responses triggered by the pain stimulus along the afferent sensitive route. Spinally the arrival of algic input activates, as a reflex, the anterior dorsal horn’s somatomotor and preganglionic neurons with subsequent hypertonic skeletal muscles and autonomic hyper-reactivity.
The hypothalamus, which is directly related with pain sensitive routes, causes suprasegmentary reflex responses that result in deep neuroendocrine alterations, which are characterized by the incretion of catabolic hormones such as catecholamines, cortisol, angiotensin II, GH and glucagon and the inhibition of anabolic hormones such as testosterone and insulin.
Lastly cortical circuits are at the basis of psychopathological processes such as anxiety, insomnia, discomfort and voluntary immobility due to the fear of aggravating pain-related symptoms that accompany the conscious perception of pain. Clinically speaking hypermetabolism leads to a negative nitrogen balance and to increased oxygen consumption.
The cardiovascular system’s involvement in the stress reaction can be extremely dangerous: catecholamines and angiotensin II can lead to myocardial ischaemia by increasing the heart’s work, while concomitant water retention promoted by aldosterone, ADH and cortisol can precipitate episodes of heart failure in patients with reduced reserves.
The respiratory system too is particularly exposed to the negative effects of pain: the accumulation of liquids in pulmonary interstices and the reflex increased skeletal muscle tone in surgical wounds located in the chest and high abdominal region can compromise normal respiratory functions and encourage the onset of pulmonary complications.
Autonomic hyperactivity is accompanied by smooth muscle paralysis with negative effects in the gastroenteric and genitourinary systems: the nausea and vomit related with post-operative ileum delay and the resumption of enteral feeding, while urinary retention exposes to the risk of infections.
Even coagulation changes in stress response: haematic hyperviscosity and platelet tendency to aggregate increase the incidence of thromboembolic events. Lastly many mediators released in response to pain depress the immune response, encouraging the onset of complications of an infectious nature. The many pain related adverse events have a negative impact on the outcome and comfort of patients: postoperative morbidity and mortality are increased and delayed action is evident in increased hospitalisation periods and costs.

TREATMENT

Physiopathological know how on the origin of pain has contributed to the clinical introduction of certain concepts, leading to progress in the traditional procedure that considered pain simply as a symptom to be treated.
The knowledge of dynamic events that amplify and also distort the painful input has introduced the concept of preemptive analgesia in antalgic treatment, in other words the need to establish precocious antalgic treatment before the onset of symptoms to prevent neurophysiological modifications, which are at the basis of peripheral and medullary hyperexcitability. It is thus possible to ensure an adequate analgesic plan by acting during the preparatory phase or however before the nociceptive stimulus begins, in order to delay or attenuate the pain-related symptoms and prevent events related with the formation of the spinal memory of pain (preemptive analgesia).
Analgesia is then continued during and after surgery on the basis of the variability of painful stimuli and related symptoms. Multimodal analgesia is another concept: it is an approach based on the combined use of multiple drugs administered with different methods and at different preoperative moments. By exploiting the synergic effect of many drugs with different methods of action the multimodal approach minimizes the side effects typical of single drug treatment and enables to intervene at various levels of the ‘pain route’, guaranteeing better quality analgesia.
Drug treatment is essentially based on three classes of drugs: NSAIDs, opioid analgesics and local anaesthetics. NSAIDs block the cyclooxygenase route, thus inhibiting the synthesis of prostaglandins (PG) involved in sensitising peripheral nociceptors and in hyperalgic events; administered systemically they are probably the most frequently used drugs to control post-operative pain. They are effective in treating mild to moderate pain, but administered alone they cannot control pain in major surgery. In these cases they can be used as adjuvants as they can lessen the discomfort and hence the side effects of opiates, thus improving the quality of the analgesia.
We must mention that NSAIDs prevent the formation of new PG, while the PG already released continue to exercise their hyperalgic effects. Hence the most effective use of non-steroid analgesics lies in the prevention of pain. The reduction of prostaglandins, which is the basis of the therapeutic effect, also causes the main undesired effects related with the use of NSAIDs: erosion/gastrointestinal ulcers, renal failure and haemorrhagic complications.
As already stated previously NSAIDs blocking the cyclooxygenase route, thus inhibiting the synthesis of PG involved in the sensitisation of peripheral nociceptors and in hyperalgic events, but the cyclooxygenase enzyme has two forms (COX-1 and COX-2). COX-1 is a representative product of healthy cells and promotes the synthesis of PG involved in normal cellular functions such as the production of gastric mucus, the maintenance of renal haematic flow and platelet aggregation. COX-2 is instead the inducible enzyme and it is produced during inflammatory conditions. PGs synthesized by COX-2 are directly involved in the modulation of the inflammatory response and of the transmission of painful stimuli. NSAIDs’ inhibition ratio between COX-1 and COX-2 will decide the appearance of undesired effects. For this reason studies have focused on identifying COX-2.4, 5 specific inhibitors. The existence of a third isoenzyme (COX-3) was recently discovered.
Experimental studies concerning its role are still underway - they could lead to new generation NSAIDs. It seems that paracetamol’s method of action, a well-known NSAID with powerful analgesic and antipyretic effects but with hardly any effects on gastric mucus and on platelets, is related with the inhibition of COX- 3. 7,8
Opiates are certainly the most powerful analgesic drugs, to the point that they represent the stronghold of antalgic treatment in moderate to severe pain as they directly act on the central systems involved in modulating the nociceptive stimulus. The effects of opioids depend on the interaction with specific receptors (¼1,¼2,º,´,Ã,µ) variously distributed in the brain and the spinal cord. The pharmacological profiles of opioid receptors are now well documented. ¼1 receptors produce analgesia by acting at a supraspinal level, while ´ and º receptors alleviate pain through spinal mechanisms. Undesired effects related with analgesic opioid treatment are none other than an extension of the pharmacological activity, especially respiratory depression, which is the most feared complication; it is a response mediated by the receptor ¼2.
Other consequences of receptor activation comprise myosis (¼1,º), feeling of well being (¼1), reduced gastrointestinal motility (¼2), nausea and vomit (¼1, ´), itching (¼1, ´), sedation (¼1, º), dysphoria and hallucinations (Ã), tolerance and physical dependence (¼1,´,º). 
Analgesic opioids are classified on the basis of the activity and attraction towards receptors as agonists, antagonists, partial agonists and mixed agonists.
Pure agonist drugs (Morphine, Meperidine, Fentanyl, Remifentanyl, etc.) are the most used in antalgic treatment.
Despite being relatively selective towards ¼ receptors they have a moderate activity on other receptor categories (º, ´), which explains their spinal and supraspinal analgesic properties and also their undesired dose-related reactions and potential additive effect. The presence of endogenous opioid peptide receptors in the dorsal horn is at the basis of these drugs’ use for spinal analgesia, which offers the advantage, when compared to the systemic route, of reaching a high drug concentration directly on the site of action. Local anaesthetics are administered to obtain both peripheral and central nervous blocks when treating acute pain.
They block action potentials that conduct the impulse by interacting with the ionic channels present in nervous fibres, thus reversibly interrupting afferent sensitive nerve endings. When they are applied to a nerve or its immediate neighbourhood they cause a total sensitive block and motor paralysis; when administered directly at a spinal level they also induce an autonomic block, with subsequent neurovegetative effects. From the moment local anaesthetics, besides blocking the conduction in peripheral nerves, also interfere with the functions of organs in which the impulse is conducted there can be adverse reactions in the CNS, myocardium, neuromuscular junctions and the entire muscular system. This danger is obviously proportionate with the drug’s plasma concentrations that are reached after absorption. Hence it is obvious that the ideal anaesthetic for postoperative analgesia must be long-acting with low systemic toxicity and it must preferentially induce a sensitive block. Ropivacaine, which boasts these features, is currently the first choice anaesthetic to be used for antalgic purposes.
Besides local anaesthetics, a block of the nervous conduction of painful stimuli in peripheral nerves and posterior roots prevents the onset of central sensitisation events. The nervous block around the surgical wound has hence the double advantage of suppressing pain and of effectively preventing sensitisation-related events. The subaracnoid route is hardly used for analgesic purposes due to the danger of infectious complications associated with the presence of a catheter in close contact with the cephalorachidean route. The epidural route, which is more suitable for continuous catheter infusion, is generally preferred.
Epidural administration of opioids and local anaesthetics ensures an adequate analgesic plan with a lower incidence of undesired effects. Since the two drugs intervene at different levels along the circuits involved in pain transmission, the association enables to use lower doses than those required if they were each used alone. The substantial advantage of introducing drugs directly into the spine has lead to study new molecules that can interfere with the medullary pain transmission process.
These also number alpha 2 agonists - the most famous one is clonidine, which is already used clinically. Alpha 2 adrenergic receptors are located on primary afferent nerve endings, bone marrow neurons and neurons of the trunk implied in analgesia. All this supports the theory of a spinal and supraspinal analgesic action. It has in practice been proved that alpha 2 agonists inhibit the excitability of primary afferent fibres and reduce the release of algogenic neurotransmitters like substance P in the dorsal horn. The locus coeruleus instead, which is in charge of sedative effects too, is supposed to be involved in supraspinal mechanisms. 11
It has recently been proved that the analgesic effect of alpha 2 adrenergic agonists could be mediated by different receptor subtypes. This theory opens the way for the study of selective drugs that only have an analgesic effect, avoiding hypotension and sedation. A special method of administration called PCA (Patient Controlled Analgesia) has been perfected due to the difficulty in controlling pain when anaesthesia wears out and the variables related with the type of surgery and individual diversities.
This method, used for intravenous, epidural and perineural administration, optimizes analgesia by enabling the patient to independently handle drug administration according to the fluctuation of painful symptoms, thanks to the availability of manual, elastomeric (fig. 2,3) and electronic pumps equipped with a control module for the self administration of additional loads. This treatment is obviously programmed by the doctor, who decides the drug type, concentration, timings and maximum dosage that can be administered (fig.4).
The choice of analgesic technique obviously depends on the intensity of the pain and the site of surgery. In mild and moderate pain the simplest approach consists in systemically administering a non-steroid, anti-inflammatory drug, associated or not with an opiate. At least during the period that directly follows surgery the intravenous route (repeated loads, continuous infusion) should be preferred to the oral or intramuscular ones as it enables to rapidly reach the effective plasma concentration. More complex techniques such as epidural analgesia must be applied in those patients for whom severe pain is expected. Continuous peripheral nervous blocks are applied in the treatment of moderate and severe pain obviously only when the use of a local/regional anaesthetic is specified.

Postoperative pain (POP)
IN ORTHOPAEDIC SURGERY

In the orthopaedic and traumatology field the treatment of acute postoperative pain is of particular importance considering certain typical features of this specialized surgery. Generally speaking orthopaedic surgery is accompanied by an impressive phlogistic and algogenic reaction, whose intensity depends on the extent of the area operated. Besides postoperative pain can influence the functional recovery of the skeletal district operated, negatively influencing the patient’s rehabilitation and outcome.
The problem concerning the expense of health services and the improvement of anaesthetic and surgical techniques has also changed the scenario of orthopaedic surgery, recording in recent years a remarkable increase in the number of outpatients’ surgery. Local/regional techniques (nervous peripheral blocks, central blocks) are extensively applied both for anaesthetic and antalgic purposes due to surgical site features. In postoperative pain control they offer the advantage of a minor endocrine-metabolic response to surgical stress and are more effective than the systemic administration of analgesics in preventing the inducement of hypersensitivity to pain, according to preemptive analgesia theories.
In upper and lower limb surgery nervous peripheral blocks (anaesthesia of the plexus, anaesthesia of the trunk) enable to obtain the best compromise between good operating conditions, adequate analgesia and the patient’s safety and comfort. However the abatement of painful symptoms is limited to at least 24 hours after surgery when a single peripheral block is applied.
The introduction of a catheter in the vascular-nervous tract when the block is created (fig.5, 6,7,8), the use of pumps for continuous infusion and for PCA techniques together with a sufficiently high therapeutic index and the availability of long-acting local anaesthetics that can selectively induce a sensitive block have enabled to prolong regional anaesthesia in the post-operative period, ensuring satisfactory results.
Many studies confirm the use of continuous perineural analgesia in certain surgical sites: reduction of hospitalisation period, minor incidence of anaesthesia related complications, better control of POP related with a reduced need for opioid or anti-inflammatory analgesics and quick functional recovery are the main advantages of this type of approach.15,16 The continuous peripheral block has proved effective and safe also in outpatient surgery.
Lumbar rachianaesthesia, both subaracnoid and peridural, is recommended in surgery of the hip and the entire lower limb. Often in orthopaedics, variables that limit indications are added to traditional contraindications: long operations, the use of bloody and noisy tools, uncomfortable posture on the operating table and the need for invasive haemodynamic monitoring.
The general preference is for balanced anaesthesia that associates general anaesthesia (hypnosis) with the epidural block (analgesia). Continuous PCA epidural infusion of opioids and local anaesthetics is certainly an effective analgesic treatment in major orthopaedic surgery. After hip prosthesis surgery 84.3% and 85.7% of patients respectively subject to balanced anaesthesia and epidural anaesthesia alone do not present pain, while moderate to severe pain is recorded in 34.3% of patients subject to general anaesthesia. 20 Epidural anaesthesia also offers good bleeding control during and after surgery and reduces thromboembolic complications, which are some of the most feared events in major orthopaedic surgery.
Besides there are no studies that make a comparison between the extent of bleeding and especially of postoperative pain in local/regional anaesthetic techniques and modern general anaesthetic methods that make use of increasingly selective anaesthetic drugs, which are effective and have an increasingly good tolerance profile.
A study still underway at the Istituto ortopedico G. Pini shows that the anaesthetic method adopted in knee arthroscopic surgery influences post-operative progress concerning pain: the important fact is that an adequate POP control is always obtained, but patients subject to general anaesthesia present a greater request for analgesics than the group that undergoes local/regional anaesthesia.
However this preliminary data reveals a difference also related to the many general anaesthesia techniques adopted (fig. 9,10). Considering local/regional techniques, the insertion of a catheter in the peridural space is an invasive manoeuvre that requires specialized manual skills and is aggravated by complications that contraindicate its use in certain patients (i.e. treatment with heparin): in these cases intravenous PCA with opioid and anti-inflammatory analgesics is a valid alternative in the treatment of severe pain.21.
We must however specify that systemically administered opioids do not alter response to surgical stress (except in dosages that significantly depress the respiratory function), while epidural analgesia, besides reducing post-operative catabolic response, also ensures dynamic analgesia, thus enabling precocious mobilization. Though local-regional techniques have proved to be a winning strategy in post-operative pain control (POP), we must not neglect the need to administer anti-inflammatory drugs systemically.
NSAIDs are essential considering the remarkable phlogistic reaction typical of orthopaedic surgery. Used alone they can check mild pain in minor surgery, while they are associated with opioid analgesics in very intense pain. But their use is limited to the need to prevent bleeding, especially in major surgery.
The recent availability of COX-2 specific inhibitors enables to overcome these limits.
Systemic drugs can obviously integrate local-regional methods when the latter prove inadequate. Concluding, orthopaedic surgery with its need to access almost all body districts represents a wide field of application for the many antalgic techniques currently available.

Renato Coluccia
Primario
Senior Consultant
Alfonso D’Aloia, Sabrina Basilico
Servizio di Anestesia, Rianimazione e Terapia del Dolore Anaesthetics, Intensive Care and Pain Therapy
Istituto Ortopedico Gaetano Pini, Milano