Eicosanoids And Cyclooxygenase Enzymes Biology Essay


Thromboxane A2 and prostaglandin endoperoxide, which are needed for the haemostatic function of platelets, are synthesized from arachidonic acid by the cyclo-oxygenase (COX) enzyme system. Non-steroid anti-inflammatory drugs (NSAIDs) inhibit the enzyme system, impairing the formation of clots and, consequently, haemostasis. NSAIDs are widely used as analgesics in the treatment of acute bone-related pain. There are two COX isoforms: COX-1 and COX-2. COX-1 synthesizes prostaglandins, which protect the gastric mucosa; COX-2 is involved with inflammatory responses. Inhibition of these systems ceases rapidly when administration of NSAIDs is stopped. Prostaglandins are known to have an important role in bone repair. Animal studies have demonstrated that both non-specific and specific inhibitors of COX impair facture healing. Some studies have suggested that this impairment results from COX-2 inhibition. This has raised concerns regarding the use of NSAIDs as anti-inflammatory or analgesic drugs in patients undergoing orthopaedic procedures, however, the clinical implication of this are probably minimal and NSAIDs remains extremely important analgesic agents for orthopaedic patients.

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The activation of phospholipase A2 by pro-inflammatory cytokines leads to a production of arachidonic acid from membrane phospholipids. Arachidonic acid gives rise to eicosanoids, physiologically and pharmacologically active compounds known as prostaglandins (PG), thromboxanes (TX), leukotrienes (LT) and lipoxins (LX). PGs are considered to sensitise the nociceptors to natural stimuli and endogenous chemicals by modifying a voltage-sensitive Na+ current specific to nociceptors (Gold et al 1996). Eicosanoids are synthesized via two pathways: the cyclooxygenase pathway and the lipooxygenase pathway. COX is the key enzyme in the synthesis of PGs, prostacyclin and TXs. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1.

Ketorolac tromethamine (Ketorolac) , a peripherally acting, non-steroidal anti-inflammatory drug (NSAID), exerts its analgesic effect at the starting point of the pain pathway by preventing sensitization of nociceptive terminals in the area of tissue injury. Acting as a competitive inhibitor (Smith et al 1991), ketorolac interrupts the arachidonic acid pathway at the level of the COX enzyme to prevent the formation of prostaglandins (Dahl and Kehlet 1991). Ketorolac is primarily metabolized by glucuronide conjugation to an inactive metabolite. Unlike morphine, whose active metabolite M6G enhances the opioid effects, all of the analgesic and side effects of ketorolac are induced by the drug and not its metabolites (Buckley and Broden 1990). As a nonspecific COX inhibitor, ketorolac inactivates both isoforms, lowering the levels of both naturally occurring prostaglandins required for essential biological processes and those prostaglandins induced (via COX-2) from injury or inflammation. Ketorolac is widely used as an analgesic in the postoperative period. Earlier studies have assessed that ketorolac 30mg intramuscular (IM) to be as effective as 12mg morphine sulphate IM in the treatment of moderate or severe postoperative pain (Yee et al 1986, O'Hara et al 1987) and a similar speed of onset (Rice et al 1991). Ketorolac also may provide analgesia of longer duration than morphine (Rice et al 1991).

Yee et al (1986) noted that the analgesic efficacy of ketorolac and morphine was better discriminated by patients who had undergone major surgery. Patients in the present study all underwent major orthopaedic surgery. Brown et al (1990) assessed that intravenous (IV) ketorolac 30mg and 10mg as efficacious as 4mg morphine IV in the treatment of moderate or severe postoperative pain.


Ketamine is extremely lipid-soluble and it is a derivative of phencyclidine. Ketamine used in low doses (0.1-0.5 mg/kg) provides the opportunity to block NMDA receptors. Postoperative administration of ketamine has been documented to not only decrease opioid consumption and improve postoperative pain control but also decrease the incidence of chronic pain syndromes several months after surgery (De kock et al 2001; Bell et al 2006).


Diclofenac sodium is one of the most potent inhibitors of the cyclooxygenase pathway. Diclofenac sodium is almost totally absorbed after oral administration, peak serum levels being attained within 2 hours of ingestion. Similar to most other NSAIDs, diclofenac is highly bound (99.7%) to serum proteins. Diclofenac administered orally, intramuscularly, or rectally in single doses of 50-100 mg is an effective analgesic agent for the treatment of minor surgical pain (Kantor 1986). IV administered diclofenac decreased the need for PCA fentanyl by about 40% after total hip replacement surgery (Laitinen and Nuutinen 1992). On the other hand, in a recent study, a continuous infusion of diclofenac failed to decrease opioid requirements in geriatric patients undergoing major orthopedic surgery (Fredman et al 2000).

Adverse effects of NSAIDs

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The major adverse effects of NSAIDs for surgical patients are those involving the gastrointestinal system, renal and platelet function, and aspirin-induced asthma in susceptible patients. The adverse effects of NSAIDs are serious and contraindications must be respected. The incidence and severity of NSAIDs-related adverse effect are greater in elderly patients.The reduced production of PGs also decreases the glomeruleric filtration. Because ketoprofen, ketorolac and diclofenac have an inhibitory effect on platelet aggregation (Niemi et al 1997), they may increase the risk of surgical site bleeding.


Morphine is a centrally acting, exogenous opioid agonist that mimics the activity of the endogenous opioid peptides. It exerts its analgesic effect by acting in 2 places along the pain pathway. First, morphine binds at µ receptors in the nociceptive synapse of the spinal cord; this inhibits the release of substance P and/or hyperpolarizing postsynaptic inter-neurons, thus decreasing the transfer of the pain signal across the synapse. Second, morphine binds to µ receptors in the brainstem, activating the descending analgesic pathway that inhibits signal transduction across the nociceptive synapse in the spinal cord (Besson J 1999).

The principal pathway of metabolism of morphine is conjugation with glucuronic acid in hepatic and extra-hepatic sites, especially the kidneys. Approximately 75-85% of a dose of morphine appears as morphine-3-glucuronide, and 5-10% as morphine-6-glucuronide. The former is pharmacologically inactive, whereas morphine-6-glucuronide produces opioid effects via its actions at µ-receptors. In fact, its potency and duration of action are greater than that of morphine, and it is possible that the majority of analgesic activity attributed to morphine is actually attributable to its morphine-6-glucuronide metabolite (Stoelting RK 1999).

The 3 major side effects of morphine are constipation, nausea and vomiting, and respiratory depression. Morphine's action on µ receptors of colonic smooth muscle cells increases tonic contractions, but reduces the rate of propulsive waves, leading to delayed transit time and constipation (Bueno and Fioramonti 1988). Nausea and vomiting are induced by morphine's activation of the µ receptors in the chemoreceptor trigger zone (CTZ) in the area postrema of the medulla; the CTZ is one of many sensory inputs that stimulate the vomiting center (Thompson H 1999). Respiratory depression (rate, tidal volumes, and carbon dioxide sensitivity) results from direct action on µ receptors of the pontine and bulbar brainstem respiratory centre that inhibit normal (reflex) responses to increasing levels of carbon dioxide (Vanegas et al 1998, Shook et al 1990).


Fentanyl, a 4-amilidopiperidine compound, is a pure opioid receptor agonist and has a selective high affinity for the µ-receptor. Unlike morphine, it has high lipid solubility which facilitates its transfer across the blood-brain barrier. Because of this lipophylic nature, fentanyl has a quicker onset of action than morphine and is 75-100 times more potent. However, when administered via the intravenous route, a single dose of fentanyl has a short duration of action, which reflects its rapid redistribution to inactive tissue sites such as fat and skeletal muscles(Stoelting RK 1999). Fentanyl is extensively metabolised in the liver to norfentanyl. The latter is excreted by the kidneys and can be detected in the urine up to 72 hours after a single intravenous dose of fentanyl. Because of its quick onset, fentanyl is well suited for intravenous patient-controlled analgesia.


Sufentanil is an analogue of fentanyl. The analgesic potency of sufentanil is five to ten times that of fentanyl. Its high tissue affinity is consistent with the lipophilic nature of sufentanil, which permits rapid penetration of the blood-brain barrier and a rapid onset of CNS effects. Sufentanil is rapidly metabolised by N-dealkylation and O-demethylation. Extensive hepatic extraction means that clearance of sufentanil will be sensitive to changes in hepatic blood flow but not to alterations in the drug hepatic blood flow but not to alterations in the drug (Stoelting RK 1999).


Pethidine (meperidine) is a synthetic opioid agonist at opioid µ- and κ-receptors. Structurally pethidine is similar to atropine and it possesses a mild atropine-like antispasmodic effect. Pethidine is about one-tenth as potent as morphine and a 10mg demand dose is equi-analgesic to 1mg of morphine. Its duration of action is 2-4 hours, making it a shorter-acting opioid receptor agonist than morphine. Extensive hepatic metabolism of pethidine leads to norpethidine. Urinary excretion is the principal elimination route of norpethidine. This metabolite is about one-half as active as pethidine as an analgesic.


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Ropivacaine is a long-acting amide local anaesthetic with a similar structure and clinical profile to bupivacaine but with less associated toxicity at comparable doses (Knudsen et al 1997). For this reason, ropivacaine is the preferred local anaesthetic for peripheral nerve blocks and continuous peripheral nerve infusions in many institutions. A comparison of continuous interscalene brachial plexus block (CISB) with 0.2% ropivacaine versus 0.15% bupivacaine revealed equivalent analgesia in both groups but significantly less motor block with ropivacaine (Borgeat 2001).

While ropivacaine is now considered the local anaesthetic of choice despite its greater cost, earlier trials used either the shorter acting lignocaine or bupivacaine. Bupivacaine has been shown to cause greater dose related central nervous system and cardiac toxicity than ropivacaine (Scott et al 1989). Ropivacaine has less motor blockade than either of these drugs (Casati et al 2003), which may be clinically important in terms of active postoperative mobilisation of the shoulder.

Ropivacaine with fentanyl

Laboratory studies have demonstrated a synergistic analgesic effect of a combination of an epidural opioid and a local anaesthetic (Kaneko et al 1994). Many clinical studies on the effect of adding low concentrations of bupivacaine to epidural fentanyl have produced conflicting results. The addition of fentanyl to epidural ropivacaine either produces lower pain scores or reduces the consumption of ropivacaine or both.


Opioids are prescribed to reduce the aversiveness of the experience of pain. Clinical trials of opioid efficacy suggest that the drugs can provide useful analgesia in the short and medium term. Data demonstrating sustained analgesic effectiveness in the longer term are lacking. Opioids can be effective in the management of somatic, visceral and neuropathic pain. Complete relief of pain is rarely achieved. The goal should be to reduce pain sufficiently to facilitate engagement with rehabilitation and the restoration of useful function.

All opioid drugs, whether naturally occurring such as morphine, or chemically synthesized, bind with specific opioid receptors to produce their pharmacologic effects. Three major classes of opioid receptors are μ, δ and κ. A fourth opioid receptor (σ) was suggested, but a variety of other non-opioid drugs also appear to act as ligands at this site so it is doubtful whether this receptor should now be considered a true opioid receptor. Further sub classification of some opioid receptors (e.g. into μ1 and μ2) is possible, but the pharmacologic and clinical significance of this remains unclear. Based on opioid interactions with these receptors, opioids fall into three main categories:

a. Pure agonists - drugs that bind to and stimulate opioid receptors, and are capable of producing a maximal response

b. Partial agonists - drugs that stimulate opioid receptors but have a ceiling effect, i.e. produce a sub-maximal response compared with an agonist

c. Mixed agonist-antagonists - drugs that are agonists for one opioid receptor but antagonise other opioid receptors.

Opioids are also classified as being 'strong' or 'weak', depending on the strength of their clinical effect, which has historically been measured against the effect of morphine. Some opioids and their classifications are listed below:

Table 1. Opioids and their classifications

Drugs bind to opioid receptors as either full agonists (e.g. morphine and methadone), partial agonists, mixed agonists (full agonist on one opioid receptor, but partial agonist on another, e.g. pentazocine and butorphanol), or antagonists, such as naloxone and naltrexone. Presently available opioids (with major opioid receptor target shown in brackets) include morphine (μ > κ), methadone (μ), etorphine and bremazocine (μ, δ and κ), levorphanol (μ and κ), fentanyl (μ) and sufentanil (mainly μ).

Opioid analgesia is spinally mediated via presynaptic and postsynaptic receptors in the substantia gelatinosa in the dorsal horn (Yaksh 1981). Spinal opioid receptors are 70% μ, 24% δ and 6% κ (Treman and Bonica 2001), with 70% of all μ and δ receptors being presynaptic (predominantly small primary afferents) and commonly co-located, and κ receptors being more commonly postsynaptic.

Intrathecal opioids

The lipid solubility of opioids largely determines the speed of onset and duration of intrathecal analgesia; hydrophilic drugs (eg morphine) have a slower onset of action and longer half-lives in cerebrospinal fluid with greater dorsal horn bioavailability and greater cephalad migration compared with lipophilic opioids (eg fentanyl) (Bernards et al 2003). Safety studies and widespread clinical experience with morphine, fentanyl and sufentanil have shown no neurotoxicity or behavioural changes at normal clinical intrathecal doses (Hodgson et al 1999).

After hip arthroplasty, 100 µg and 200 µg doses of intrathecal morphine produced good and comparable pain relief and reductions in postoperative morphine requirements; 50 µg was ineffective (Murphy et al 2003 ).

In a more recent study, intrathecal sufentanil provided shorter postoperative analgesia (mean 6.3 hours) than intrathecal morphine (mean 19.5 hours) with no difference in side effects (Karaman et al 2006).

Extended release epidural morphine (EREM) has been shown to be effective compared with placebo after hip arthroplasty (Viscusi et al 2005; Martin et al 2006) and, using doses of 10 mg or more, to lead to better pain relief compared with standard epidural morphine (4 or 5 mg) and a reduction in the need for supplemental analgesics up to 48 hours after hip arthroplasty (Viscusi et al 2006).

Intra-articular bupivacaine was less effective than morphine in providing analgesia in patients having 'high inflammatory arthroscopic knee surgery', whereas bupivacaine was more effective than morphine in those having 'low inflammatory surgery' (Marchal et al 2003)

Alpha-2 agonists

Clonidine is an alpha-2 adrenoceptor agonist that acts as an analgesic at the level of the spinal cord. Its main clinical effect is the reduction of blood pressure. Intrathecal clonidine given in doses from 15 to 150 µg combined with intrathecal local anaesthetic, significantly prolonged the time to two segment block regression but did not affect the rate of onset of a complete block (Elia et al 2008).The addition of clonidine to PCEA with ropivacaine and morphine after total knee arthroplasty decreased opioid requirements and improved analgesia without increasing side effects. The addition of clonidine to epidural levobupivacaine, also after hip arthroplasty, significantly reduced postoperative morphine requirements compared with either drug alone (Milligan et al 2000).

Epidural opioids

The behaviour of epidural opioids is also governed largely by their lipid solubility. Lipophilic opioids (eg fentanyl) have a faster onset but shorter duration of action compared with hydrophilic drugs (eg morphine) (Bernards 2004).

Morphine is the least lipid soluble of the opioids administered epidurally; it has the slowest onset and offset of action and the highest bioavailability in the spinal cord after epidural administration (Bernards 2004).

Pethidine is effective when administered epidurally by bolus dose, continuous infusion and by PCEA. It is more lipid soluble than morphine (but less than fentanyl and its analogues), thus its onset and offset of epidural analgesic action is more rapid than morphine (Ngan Kee 1998).

Diamorphine (diacetylmorphine, heroin) is rapidly hydrolysed to monoacetyl-morphine (MAM) and morphine. Diamorphine and MAM are more lipid soluble than morphine and penetrate the central nervous system (CNS) more rapidly, although it is MAM and morphine that are thought to be responsible for the analgesic effects of diamorphine (Miyoshi and Lackband 2001). Epidural administration of diamorphine is common in the United Kingdom and is effective whether administered by intermittent bolus dose or infusion (McLeod et al 2005).

Patient-controlled analgesia

PCA stands for patient-controlled analgesia. It means that you can have control over your own pain relief using pain medicines such as morphine or fentanyl. When you start to feel uncomfortable, you press a button attached to a PCA pump. The pump then injects a small dose of the medicine into an intravenous (IV) cannula in your vein. Your doctor (often your anaesthetist) will order the amount of pain medicine delivered by the PCA pump each time you press the button. By programming the right amount for you, the risk of severe side effects is very low. You should press the PCA button when the pain starts to become uncomfortable. You should not wait for the pain to become very severe. Macintyre (2001) reported that PCA does not always provide optimal pain relief due to inadequate analgesia prior to commencement of the PCA and a lack of individualisation of PCA prescription to provide maximum benefit for the patient (Macintyre PE 2001).

In addition, several studies have revealed a consistent lack of effect of PCA on surgical stress responses and organ dysfunction when compared with epidural analgesia techniques (Kehlet H 1997).

Regional anaesthesia

Regional anaesthesia, either alone or in combination with a general anaesthetic, has become increasingly used for joint replacement surgery owing to the benefits it offers over an opioid-based general anaesthesia technique. Some of its benefits include the following;

a. Reduced incidence of postoperative deep vein thrombosis and pulmonary embolus in lower limb arthroplasty (owing to a sympathectomy- induced increase in blood flow and antagonism of the hypercoagulable state)

b. Reduced intraoperative blood loss (reducing the requirement for blood transfusion)

c. Reduction in the effects of general anaesthesia and systemic opioid analgesia on pulmonary function (basal atelectasis, hypoxaemia and pulmonary infection) and reduced incidence of postoperative nausea and vomiting.

d. Improved postoperative analgesia compared with general anaesthesia.

e. It may avoid the need for endotracheal intubation and the consequent vasopressor response.

f. Enhanced early postoperative rehabilitation and improved outcome from surgery (especially shoulder and knee arthroplasty).

Regional anesthesia is an alternative to general anesthesia for major surgery on the extremities or the lower abdomen. The choice as to whether to use regional or general anesthesia is based on surgical procedure, surgical and anesthesiologist skill and experience, as well as the patient's medical status and preference. Regional block techniques can be combined with general anesthesia so as to reduce the concentration of general anesthetic used, and to improve postoperative analgesia. However, except for some specific surgery (e.g. Cesarean section, transurethral prostatectomy, hip and knee surgery in the elderly), regional anesthesia is not necessarily safer than general anesthesia. General anesthesia always becomes necessary if regional anesthesia fails.

Regional anaesthesia and nerve blocks are widely used in children, although mostly in conjunction with general anaesthesia. However, important differences are found in children and must be remembered when regional techniques are performed. Children and especially small infants are less resistant to local anaesthetic toxicity than adults due to:

Rapid heart rates which predisposes to bupivacaine accumulation in the heart.

Reduced levels of α 1 acid glycoprotein in neonates that binds local anaesthetic.

Current data for anaesthetic techniques used in England and Wales for lower limb joint replacements are summarized in the following table below (these data include combinations of techniques).

Table 1. Anaesthetic techniques used for joint surgery in England in 2005 (adapted from National Joint Registry Data, 2006)

Epidural analgesia

Pain medicines (often a mixture of local anaesthetic and opioid) can be given through a small tube placed in your back and into the epidural space. This space is close to the spinal cord and the nerves that come out from the spinal cord. These nerves mean you can feel things such as pain. The tube is called an epidural catheter. It can also be used to manage acute pain after some operations and injuries. For example: after chest surgery and major operations on hips or knees or broken ribs.

Choi et al (2003) reviewed the evidence comparing the efficacy of epidural analgesia with other postoperative modalities for pain relief following hip or knee replacement. The authors conclude that epidural analgesia may be useful for postoperative pain relief following major limb joint replacements; however, the benefit may be limited to the early (four to six hours) postoperative period. Epidural anesthesia can also alter the effect of intra-articular morphine, for at least two reasons. First, epidural anesthesia has been shown to substantially blunt the neuroendocrine response to surgical trauma asn to reduce the release of several inflammatory mediators. Furthermore, it can produce a pre-emptive and prolonged postoperative analgesic effect.

Epidural analgesia can give the best pain relief of all. This may reduce the risk of problems after surgery in some patients. Good pain relief can help people to breathe and cough well. So, it may be of benefit in patients who are elderly or who have major medical problems. It may also be good for patients having major surgery.

Complications can occur and Most of these are minor and easily treated. More serious ones can also happen but these are very rare.

Multimodal analgesia

It has been recommended this analgesia is used in a multimodal fashion in the post-operative period. The approach involves in the combination of various analgesics such as paracetamol, NSAIDs, opioids and local anaesthetics, used in smaller doses to provide a better pain relief with fewer side effects and less need for opioids (Myles et al 2007; Pasero et al 2003).

Interscalene brachial plexus blockade

The interscalene brachial plexus block (ISB) alone or in combination with general anaesthesia is a very suitable technique for shoulder surgery. In this technique, the interscalene groove is palpated at the level of C6. After the groove is identified, a needle is inserted perpendicularly to all planes, directed caudally and advanced slowly until paresthesia below the level of the shoulder is detected. It has later been shown that the plexus can be well identified using a nerve stimulator to determine the accurate spot for the injection of local anaesthetic (Tuominen et al 1987a). In a recent report, the incidence of short- and severe long-term complications was 0.4%. When a continuous technique with placement of a catheter into the interscalene space was used, the rate of complications was not increased. (Borgeat et al 2001).

Interscalene Nerve Block

An interscalene nerve block offers some advantages over general anaesthesia for both open and arthroscopic surgical procedures. This block provides excellent intraoperative anaesthesia, muscle relaxation, and postoperative analgesia ( Wu et al 2002). Although sedation is sometimes needed during block placement, it is well accepted by patients. The interscalene nerve block is an effective shoulder anaesthetic technique. However, the best results demand a high level of expertise and familiarity.

Suprascapular Nerve Block

The suprascapular nerve block is another type of peripheral nerve block. The suprascapular nerve arises from the superior trunk of the brachial plexus. It innervates up to 70% of the posterior shoulder joint and provides innervation to the acromioclavicular joint, subacromial bursa, and coracoclavicular ligament, along with the lateral pectoral nerve.

Regional blockade techniques have a number of common complications. These include persistent paresthesia, nerve damage, inadvertent intravascular injections, and local anesthetic toxicity.

Subacromial bursa block

Vangsness et al (1995) have studied the neural histology of the human shoulder and have found scattered free nerve endings throughout the subacromial bursa. Irritation of the subacromial space with hypertonic saline solution has been shown to produce pain in the region of the lateral acromion, the deltoid muscle, and occasionally in the forearm or the fingers (Gerber et al 1998). Corticosteroids have been injected into this bursa for the treatment of symptomatic subacromial impingement syndrome (Blair et al 1996). Even though the subacromial bursa offers a suitable compartment for the injection of a drug, there are only a few studies in the literature assessing the analgesic efficacy of a local anaesthetic injection to the subacromial bursa. In a recent study, a patient-controlled, continuous infusion of lidocaine to the subacromial space appeared to be a safe method for achieving high levels of pain control in patients undergoing an acromioplasty (Mallon et al 2000).


In orthopaedic surgery, regional analgesia may also provide a functional benefit, allowing better physiotherapy. This may result in a significant shortening of convalescence after total knee replacement (Capdevial et al 1999).

After orthopaedic surgery, trials and meta-analyses have failed to document a decrease in the incidence of cognitive dysfunction or respiratory and cardiovascular complications in patients receiving epidural analgesia (Block et al 2003).

Compared to i.v patient-controlled analgesia (PCA) for open shoulder surgery, randomized, controlled trials have demonstrated that the use of a continuous interscalene brachial plexus block (CISB) reduces the postoperative requirements for opioids and provides better analgesia, reduced opioid-related side effects, and better patient satisfaction for at least the first 48 h after surgery (Borgeat et al 1997; Borgeat et al 1998).

After hip fracture surgery, epidural analgesia with bupivacaine and morphine also provided better pain relief both at rest and with movement, but this did not lead to improved rehabilitation (Foss et al 2005). PCA is an effective method of pain relief in older people (Mann et al 2003).

Following hip and knee arthroplasty, intrathecal morphine (100 to 300µg) provided excellent analgesia for 24 hours after surgery with no difference in side effects; after hip arthroplasty only there was a significant reduction in postoperative patient-controlled (PCA) morphine requirements (Rathmell et al 2003).

Epidural morphine provides analgesia without sensory, motor, or sympathetic block. Compared with systemic morphine administration, it also offers better and longer pain relief with a smaller dose and fewer side effects.

A misconception exits that the elderly feel less pain. Older people, however, need smaller dose of analgesic drugs to achieve effective pain relief. There is considerable variation between individuals so it is necessary to plan for each patient individually.


Before an analgesic is to be given, it is appropriate to assess the current intensity of pain (at rest and on movement), and the subsequent improvement that is achieved by that agent. Analgesic drugs are now used in combination in order to get the best results. Spinal diamorphine provides the best analgesia following major joint surgery and is safe to use in patients managed on a general ward, providing adequate monitoring is available. Nonsteroidal anti-inflammatory drugs (NSAIDs) are an effective treatment to decrease surgical and post-trauma pain. NSAIDs and opioid analgesics have a synergic effect, thereby achieving better pain control and an opioid-sparing effect, with fewer adverse events. Epidural morphine, which is the prototypical hydrophilic opioid, produces excellent analgesia of long duration and an extended dermatomal activity with doses much lower than those required parenterally. It has been widely used for postoperative pain relief. Local Anaesthetic nerve blockade may also provide good postoperative analgesia without the need for opioid administration. Regional techniques, especially spinal analgesia, are used in the elderly, making effective postoperative analgesia easier to achieve. Recent evidence suggests that spinal and epidural anaesthesia may decrease the postoperative morbidity and mortality.