Cns drugs 2007; 21 (3): 185-21

CNS Drugs 2007; 21 (3): 185-211  2007 Adis Data Information BV. All rights reserved.
Perioperative Pain Management
Srinivas Pyati and Tong J. Gan
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA The under-treatment of postoperative pain has been recognised to delay patient recovery and discharge from hospital. Despite recognition of the importance ofeffective pain control, up to 70% of patients still complain of moderate to severepain postoperatively.
The mechanistic approach to pain management, based on current understand- ing of the peripheral and central mechanisms involved in nociceptive transmis- Pyati & Gan sion, provides newer options for clinicians to manage pain effectively. In thisarticle we review the rationale for a multimodal approach with combinations ofanalgesics from different classes and different sites of analgesic administration.
The pharmacological options of commonly used analgesics, such as opioids,NSAIDs, paracetamol, tramadol and other non-opioid analgesics, and their com-binations is discussed. These analgesics have been shown to provide effectivepain relief and their combinations demonstrate a reduction in opioid consumption.
The basis for using non-opioid analgesic adjuvants is to reduce opioid con- sumption and consequently alleviate opioid-related adverse effects. We reviewthe evidence on the opioid-sparing effect of ketamine, clonidine, gabapentin andother novel analgesics in perioperative pain management. Most available datasupport the addition of these adjuvants to routine analgesic techniques to reducethe need for opioids and improve quality of analgesia by their synergistic effect.
Local anaesthetic infiltration, epidural and other regional techniques are also usedsuccessfully to enhance perioperative analgesia after a variety of surgical proce-dures. The use of continuous perineural techniques that offer prolonged analgesiawith local anaesthetic infusion has been extended to the care of patients beyondhospital discharge.
The use of nonpharmacological options such as acupuncture, relaxation, music therapy, hypnosis and transcutaneous nerve stimulation as adjuvants to conven-tional analgesia should be considered and incorporated to achieve an effective andsuccessful perioperative pain management regimen.
The severity and frequency of postoperative pain ry surgery.[9] Higher levels of postoperative pain can depends on the site, nature and extent of surgery.
result in poor patient satisfaction, impair quality of Despite improvements in the understanding of pain recovery and increase healthcare costs.[10,11] Several mechanisms and the introduction of acute pain ser- clinical studies[12-14] support the notion that an ap- vices, the under-treatment of postoperative pain has proach based on the use of multimodal techniques to been recognised as an important issue.[1] The litera- manage postsurgical pain is the most effective strat- ture indicates that up to 75% of postsurgical patients egy for achieving optimal analgesia.
have reported pain and 80% of these patients exper- In this article, we provide a review of current ienced severe pain at some time during their hospital strategies for the management of postoperative pain stay.[2] A recent survey also demonstrated that ap- focusing on various analgesics and analgesic tech- proximately 70% of patients still have moderate or niques. To prepare the article we performed a search severe pain during the perioperative period.[3] Pro- of MEDLINE (1980–2006) and the Cochrane libra- fessional care providers have been noted as not ry (1980–2006) to identify published reports of believing that patients have pain,[4] and the lack of randomised controlled trials and systematic reviews.
adequate knowledge and misinformation on pain The search terms used were ‘postoperative', ‘pain', management among nurses has been identified.[5] ‘analgesics', ‘analgesia', ‘mechanisms', ‘opioid', Poorly controlled acute pain can result in in- creased catabolism, increased cardiorespiratory ‘NSAIDs', ‘COX-2 inhibitors', ‘tramadol', work, immunosuppression[6] and coagulation distur- ‘paracetamol', ‘adjuvants', ‘regional', ‘epidural', bances.[7,8] Pain and postoperative nausea and vomiting prolong recovery and discharge times and ‘acupuncture', ‘TENS', ‘music', ‘hypnosis' and ‘re- contribute to unexpected admission after ambulato-  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management 1. A Mechanistic Approach to
nociceptors. These nociceptors have little spontane- ous activity under normal conditions but exhibitincreased activity, with an increase in response mag-nitude to noxious stimuli or enhanced receptive 1.1 Mechanisms of Pain field, when tissue injury occurs.[16] A complete re-view of acute pain mechanisms is beyond the scope A rational approach to the treatment of pain of this article.
would be to identify the contributing mechanismsand specifically target treatment (figure 1). Despite 1.1.1 Peripheral Mechanisms
recent progress in understanding nociceptive patho- It is recognised that inflammatory response to physiology, wide variations in the management of tissue injury results in the activation of a cascade of postoperative pain are still observed. This may, in events leading to peripheral and central sensitisation part, be due to the combination of innate individual of the nociceptive pathway (figure 2). Noxious stim- and surgical factors that contribute to the develop- ulation causes selective release of peptides and non- ment of pain. Nociceptive and inflammatory stimuli peptides in peripheral tissues, which sensitise the result in diverse effects, including nociceptive trans- peripheral nerve endings (table I). The source of duction, sensitisation of peripheral nerve endings these substances is varied: injured cells, nociceptors, and central neuronal sensitisation (figure 2).[15] enhanced capillary permeability and generation by Rarely, a single mechanism may contribute to the local enzyme activity. These substances are also pain state; more often, a combination of mecha- released in the spinal cord, resulting in sensitisation.
nisms is involved.
For example, substance P is synthesised in the neu- This section primarily focuses on the common ronal cell bodies in the dorsal root ganglion and mediators involved in the transmission and augmen- transported to peripheral and central terminals tation of noxious stimuli. Most of the nociceptive where it is stored in vesicles.[17] It causes vasodilata- signals arise from the activation of polymodal tion, oedema and the release of histamine. Substance Perception of pain
Subarachnoid opioids Local anaesthetics local anaesthetics Fig. 1. Action of analgesics at various sites of the pain pathway. COX = cyclo-oxygenase.
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CNS Drugs 2007; 21 (3) Pyati & Gan cascade (PG, LT, BK) Nociceptor activation NMDA receptor activation Neural plasticity or chronic pain
Fig. 2. Mechanism of peripheral and central sensitisation. BK = bradykinins; LT = leukotrienes; NO = nitric oxide; PG = prostaglandins.
P appears to have a role in potentiating both excita- excitation of nociceptive afferents via the activation tory and inhibitory inputs in the spinal cord, thereby of its membrane-bound receptors (5-HT1-3)[25] as sensitising the neurons to nociceptive signals.[18] It well as sensitising nociceptors, especially to has a slow and prolonged effect during sustained bradykinin.[26] Antagonists acting at peripheral sero- noxious stimulation, binding at neurokinin NK1 re- tonin receptors (5-HT2A and 5-HT3) may be of ceptors and resulting in calcium ion influx into value in reducing pain arising from inflamed tissues.
neuronal cells. Substance P also induces the produc-tion of nitric oxide, a vasodilator for the endotheli- 1.1.2 Central Mechanisms
um, which, by complex mechanism, exacerbates In recent years, major developments have been pain.[19] This finding indicates a potential role for made in our understanding of the role of the spinal selective substance P antagonists with high affinity cord in nociceptive transmission. Peripheral sen- for NK1 receptors to prevent the prolongation of sitisation can enhance the pain responses of nocicep- nociceptive transmission.[20-22] However, studies to tive neurons in the CNS. One strategy to reduce pain date have not found significant and consistent anal- arising from such a mechanism is to decrease the gesic properties for NK1 receptor antagonists in excitability of these central neurons. There are also a humans.[23,24] Serotonin – which is released from number of peptides involved in augmentation of non-neuronal cells such as platelets and mast cells nociception at the spinal level (figure 2). For exam- and within the digestive tract – is one of the compo- ple, cholecystokinin (CCK) found in intrinsic spinal nents of the ‘inflammatory soup' present in the neurons is believed to play a role in nociception and extracellular space of injured tissues. The role of selectively reduces the analgesic actions of mor- serotonin in nociception is complex. It can cause phine.[27,28] This indicates that CCK antagonists may  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management enhance opioid analgesia while reducing opioid tol- rehabilitation programmes.[42] The lack of effect of multimodal analgesia may also be due to inappropri- In vitro studies have shown that both A-beta and ate timing of administration of analgesics. Although C fibre activation increases aspartate and glutamate there is insufficient evidence to recommend pre- outflow at the level of the spinal cord,[29,30] resulting emptive analgesia routinely, it is prudent to attenu- in amplification and prolongation of nociceptive ate postoperative pain as effectively as possible dur- signals leading to a chronic pain state (figure 2). The ing the intraoperative period and initiate effective action of these amino acids[31] is mediated via analgesic therapy in the early phase of the periopera- NMDA and non-NMDA receptors. Ketamine (at tive period.
subanaesthetic doses of 0.15–0.5 mg/kg) and dex- The effectiveness of individual analgesics can be tromethorphan[32] are clinically effective NMDA re- enhanced by combining those acting via different ceptor antagonists.[33] mechanisms, such that additive or synergistic effects There is also a growing body of evidence from are achieved. For example, the synergism between animal studies[34-37] which indicates that ascending α-adrenergic and opioid systems has been demon- nociceptive and descending noradrenergic pathways strated, with the finding that clonidine can potentiate play a critical role in modulation of pain at various the effects of morphine.[43] Similarly, combinations levels in the spinal cord. The spinal receptor target of paracetamol (acetaminophen) and NSAIDs pro- for this system is the α2-adrenoceptor. Agonists at vide additive analgesic effect in mild to moderate this receptor, such as clonidine, produce anti- acute pain.[44] The addition of cyclo-oxygenase-2 nociception and may potentiate the actions of mor- (COX-2) inhibitors or NSAIDs to opioids reduces opioid requirements by 20–30%, with a concomitant As pain mechanisms rely on different receptor reduction in opioid-related adverse effects and bet- systems, it is prudent to adopt a multimodal ap-proach to achieve pain relief in the perioperative Table I. Inflammatory pain mediators
2. Rationale for Multimodal Analgesia
Calcitonin gene-related peptide The ideal postoperative analgesic regimen would provide effective pain relief, reduce opioid-related adverse effects and the surgical stress response, and improve clinical outcome, e.g. morbidity, mortality and duration of hospital stay. The concept of mul- timodal analgesia was introduced to achieve these goals by combining various analgesic techniques and different classes of drugs to improve postopera- tive outcome.[39] However, available data are con- flicting and do not necessarily show that multimodal analgesia has resulted in improved outcome and concomitant reduction in the adverse effects of opioids.[12,40,41] The failure to improve clinical out- come may be due to inappropriate combination and dosages of analgesics. In addition to adequate anal- gesia, postoperative morbidity and duration of hos- pital stay depend on other factors such as initiation of early nutrition, mobilisation and comprehensive TNF = tumour necrosis factor.
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CNS Drugs 2007; 21 (3) Pyati & Gan ter analgesia. For example, in a recent study, pa- fects compared with a local anaesthetic or opioid tients undergoing total abdominal hysterectomy alone.[56] In addition to local anaesthetics andopioids, a number of adjuvants such as ketamine[47] who were randomised to intravenous administrationof parecoxib 40mg at induction of anaesthesia had a and clonidine[57] have also been used epidurally; significant reduction (by 26%) in 24-hour morphine however, there are conflicting reports about the consumption and lower pain scores on sitting up value of epidural analgesia in improving outcomes.
in comparison with placebo.[45] Furthermore, ke- In a study of patients undergoing abdominal aortic tamine, an NMDA receptor antagonist, has been surgery receiving thoracic epidural analgesia, the shown to reduce the pain scores and lower analgesic incidence of thrombotic, infectious and cardiovascu- requirement when added to a multimodal epidural lar complications as well as the duration of hospital analgesia.[46] Adding ketamine to patient-controlled stay was significantly reduced.[58] Furthermore, the epidural analgesia (PCEA) with morphine, bupiva- combination of epidural analgesia and NSAIDs ini- caine and adrenaline (epinephrine) has been demon- tiated in the preoperative period has been shown toshorten recovery time.[14] Conversely, in high-risk strated to result in an enhanced analgesic effect – the patients who received perioperative epidural analge- mean visual analogue scale score for pain in the sia for major abdominal surgery, Peyton et al.[59] ketamine group during movement and cough were showed no difference in the duration of intensive lower than the control group.[47] The cumulative care or hospital stay, although the findings of this total analgesic consumption in the ketamine group study raise questions about its design and conclu- was also lower by 30% than the control group 24 hours following surgery. In another study, it was In some patients, the adverse effect profile of demonstrated that the combination of intraoperative various analgesics may affect quality of recovery.
ketamine and epidural analgesia may confer a long- Continuous perineural techniques offer the potential term benefit in reducing the incidence of chronic benefits of prolonged analgesia, reduced opioid re- quirements and fewer adverse effects. A prospective Similarly, transcutaneous electrical nerve stimu- evaluation of over 1300 patients undergoing total lation (TENS) administered in an optimal frequency hip arthroplasty who received continuous peripheral (85Hz) in the wound area can reduce analgesic nerve block reported significantly higher satisfac- consumption for postoperative pain. In a meta-anal- tion, fewer adverse effects and less opioid consump- ysis, Bjordal et al.[49] reported that TENS resulted in tion compared with groups that received intravenous a mean reduction in analgesic consumption by 26% patient-controlled analgesia (PCA) with morphine compared with placebo.
In addition to a reduction in total analgesic con- sumption and better pain scores, reports suggest that 3. Pharmacological Options and
multimodal analgesia may confer long-term benefits in patient outcomes.[50-52] Evidence also suggeststhat inadequate postoperative pain relief may result in significant morbidity that leads to an increase inhealthcare costs due to unanticipated hospital ad- Opioids are effective analgesics for moderate to mission.[53,54] Epidural analgesia using local anaes- severe pain, although their efficacy is limited by thetics and opioids is widely practiced as an impor- adverse effects. They act on opioid receptors in the tant component of a multimodal approach to control periphery[62,63] and CNS.
postoperative pain and hasten recovery.[55] The syn- Opioids and/or NSAIDs combined with local an- ergistic effect of a combination of local anaesthetics aesthetic infiltration or intra-articular block may be and an opioid such as morphine provides superi- a useful technique for controlling pain in patients or dynamic analgesia with minimal adverse ef- after ambulatory surgery. In most studies, local an-  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management aesthetic infiltration with systemic opioids or regular regimen of oral or rectal paracetamol.[71] It NSAIDs showed improvement in analgesia, better has been shown that 1g of propacetamol results in a recovery[9] and shortening of discharge time from significant reduction in postoperative morphine con- day surgery unit compared with placebo.[64,65] A sumption over a 6-hour period.[72] A meta-analysis prospective 7-year survey of nearly 6000 patients of analgesic efficacy suggested that paracetamol and revealed that a high degree of patient satisfaction tramadol is an effective analgesic combination in and low incidence of adverse effects could be dental and postsurgical pain; however, more patients achieved with the administration of neuraxial opioid experienced adverse effects such as dizziness, nau- analgesia for major surgery.[66] sea and vomiting with this combination than witheither agent alone.[73] Recently, a novel extended-release morphine for- mulation (morphine in a lyposomal carrier; De- Propacetamol, a prodrug of paracetamol, may be poDur;1 Endo Pharmaceuticals Inc., Chadds Ford,
a viable alternative to NSAIDs in the perioperative PA, USA) has become available for single-dose period in minor surgery.[74] epidural use. Several studies in various surgical procedures such as knee replacement, abdominalsurgery and caesarean sections have examined the NSAIDs have become the cornerstone in the efficacy of this formulation as an alternative to treatment of acute pain in the early postoperative conventional intravenous opioid analgesia.[67-69] Ex- period because of their opioid-sparing effect.[75] Ad- tended-release morphine has been reported to pro- ministration of ibuprofen and oxycodone in combi- vide analgesia up to 48 hours postoperatively for nation provides superior and effective analgesia in lower abdominal surgery.[68] Patients treated with the postoperative period.[76] The combination of 10, 20 and 25mg used significantly less fentanyl via ibuprofen and paracetamol has also been reported to the intravenous PCA system than patients receiving reduce the need for early analgesia by up to 34% in standard epidural morphine. Most frequently report- children undergoing tonsillectomy.[77] ed adverse effects were nausea, pruritus, pyrexia,vomiting and hypotension. In the extended-release morphine group who received 25mg, a decrease There has been a renewed interest in the use of from baseline respiratory rate was observed and COX-2 inhibitors for postoperative pain. Because of sedation was more pronounced up to 12 hours pos- their favourable adverse effect profile, COX-2 in- toperatively than in groups that received lower hibitors provide a safer alternative to conventional doses. Delayed respiratory depression is the most NSAIDs. Nonselective NSAIDs are associated with serious adverse effect of morphine. The authors adverse effects related to COX-1 inhibition, which recommended the optimal dose with fewer adverse include gastrointestinal ulceration, renal dysfunc- effects to be 15mg of extended-release morphine, tion and perioperative bleeding.[78] At normal doses, and that dose reduction is warranted in older pa- the COX-2 inhibitors selectively inhibit COX-2. Inaddition, they exhibit an opioid-sparing effect[79] and therefore constitute an important component of 3.2 Paracetamol (Acetaminophen) multimodal therapy for the treatment of postopera-tive pain.
Paracetamol is an effective analgesic for mild to Parecoxib (a prodrug of valdecoxib) has analge- moderate pain, with a favourable adverse effect sic potency similar to that of ketorolac and has been profile.[70] It is an effective adjuvant to opioid anal- studied extensively in postoperative dental pain and gesia, and a reduction in opioid requirement by other models.[80-84] Single-dose parecoxib 40mg pro- 20–30% can be achieved when combined with a vided significantly better pain responses compared The use of trade names is for product identification purposes only and does not imply endorsement.
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CNS Drugs 2007; 21 (3) Pyati & Gan with placebo or morphine 4mg and was comparable NSAID used and on the presence or absence of an to ketorolac 30mg after gynaecological surgery.[85] inflammatory process.[93] Romsing et al.[94] investi- The main advantage of parecoxib is that it can be gated the evidence for a peripheral analgesic effect administered intraoperatively and immediately post- of local infiltration with NSAIDs. Five studies com- operatively before oral medication is tolerated. Gan pared intra-wound infiltration of tenoxicam (7.5 or et al.[79] have shown that preoperative parecoxib 10mg) or ketorolac (30 or 60mg) with similar sys- followed by postoperative oral valdecoxib reduces temic (intravenous or intramuscular) administrationin patients undergoing inguinal hernia repair or mas- opioid requirements after laparoscopic cholecystec- tectomy. Two of the five trials showed significantly tomy compared with placebo. The cumulative mor- lower pain scores at 2 hours and 24 hours after phine equivalent dose (MED) of fentanyl in the wound infiltration with NSAIDs. The 24-hour con- treated group was lower compared with the placebo sumption of supplementary analgesics was signifi- group up to 4 days postoperatively. In addition, cantly reduced by approximately 60% in the wound significantly reduced incidences of opioid-related infiltration group. It should be emphasised that the symptoms were observed in the parecoxib/valde- observed benefit may be due to a systemic effect of coxib group.
the locally administered NSAID.
In another study, patients undergoing knee re- placement surgery were randomly assigned to re-ceive another COX-2 inhibitor rofecoxib or placebo perioperatively in conjunction with PCEA. It wasshown that the rofecoxib group experienced signifi- Tramadol is a synthetic, centrally acting analge- cantly less breakthrough pain and fewer adverse sic with weak agonist activity at opioid receptors. It effects compared with the placebo group. They also also inhibits serotonin and noradrenaline (nore- experienced quicker recovery based on range of pinephrine) reuptake.[95] The tramadol metabolite, motion and pain scores.[14] O-desmethyl tramadol, is a more potent analgesic Recently, much attention has focused on the ulti- than tramadol.[96] Unlike other opioids, tramadol mate risk-benefit ratio of COX-2 inhibitors.[86-88] lacks respiratory depressant effects and exhibits a Selective COX-2 inhibitors – by decreasing vasodi- lower risk of bowel dysfunction[97] at conventional latory and anti-aggregatory prostacyclin (epopros- tenol) production – may lead to increased prothrom- Moore and McQuay,[98] in a meta-analysis, com- botic activity. By doing this, they may affect the pared single oral doses of tramadol alone with a balance between prothrombotic and antithrombotic combination of standard analgesics (aspirin/codeine eicosanoids,[89] resulting in an increased risk of my- and paracetamol/propoxyphene) in post-surgical ocardial infarction. However, this theory was con- and dental pain. Tramadol 100mg and 150mg sidered oversimplified and the underlying mecha- showed a number-needed-to-treat value of 4.8 and nism may be more complex.[90-92] As a result of the 2.4, respectively, compared with 3.6–4.0 with com- increased cardiovascular risks, rofecoxib and bination analgesics. Frequencies of adverse effects valdecoxib have been withdrawn from the market.
were higher with increasing doses of tramadol.
Celecoxib is available for clinical use worldwide, A meta-analysis[99] of a paracetamol and tra- while parecoxib is only available outside the US.
madol combination confirmed superior analgesia NSAIDs and COX-2 inhibitors are also known to without additional toxicity. The most common ad- reduce peripheral nociceptor discharge by reducing verse effects noted were diziness, headache, nausea the local concentration of arachidonic acid metabo- and vomiting. Another study noted that the combi- lites. NSAIDs exhibit central and peripheral analge- nation of tramadol with paracetamol increased the sic action that varies depending on the type of tolerability of tramadol.[100]  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management used as an adjuvant to epidural analgesia.[115] Pa-tients who were treated with a ketamine patch after There has been renewed interest in the role of minor gynaecological surgery showed prolonged ketamine in enhancing postoperative analgesia. Sev- time to first rescue analgesia.
eral studies have focused on demonstrating the use In essence, ketamine has found a role in the of subanaesthetic doses of ketamine for various sur- management of acute pain but its use as an analgesic gical procedures to enhance pain relief and reduce has been limited by its unpleasant and unpredictable total analgesic consumption.[101-106] Central excitato- adverse effects; however, lower doses of ketamine ry neurotransmitters acting on NMDA receptors have not been found to be associated with these have been identified to be involved in the develop- ment and perpetuation of pathological pain statescausing hyperalgesia and allodynia.[107] Ketamine acts as an antagonist at the NMDA receptor.
There is much evidence (table II) to suggest that ketamine has an opioid-sparing effect and may con- The α2-adrenoceptor agonists, clonidine and fer advantages in patients in whom high postopera- dexmedetomidine,[117] have anti-nociceptive activity tive opioid consumption is anticipated. At low via peripheral, supraspinal and primarily spinal cord doses, ketamine can provide improved analgesia in mechanisms including activation of postsynaptic opioid-resistant pain.[108] Continuous infusion of α2-adreoceptors of descending noradrenergic path- ketamine has been used perioperatively. Adam et al.[109] evaluated intravenous ketamine with an ini- Epidural clonidine has several potential advan- tial bolus (0.5 mg/kg) followed by continuous infu- tages over epidurally administered local anaesthet- sion of 3 µg/kg/min intraoperatively in combination ics and opioids because it is devoid of some of the with continuous femoral nerve block in patients adverse effects associated with these drugs such as undergoing total knee arthroplasty. In this multi- motor block, urinary retention, respiratory depres- modal approach, the ketamine group required signif- sion and pruritus. In addition, clonidine exhibits a icantly less morphine than patients receiving only synergistic action when used as an adjuvant to local femoral nerve block and tolerated early mobilisation anaesthetics or opioids, resulting in a reduction in of the knee.[109] postoperative analgesic requirement.[57,118] Paech et A systematic review[113] of randomised double- al.[119] have demonstrated that postoperative epidu- blinded trials involving epidural ketamine added to ral analgesia (with bupivacaine and fentanyl) is en- various opioid-based regimens suggested improved hanced significantly by the addition of clonidine.
analgesia with no increase in ketamine-associated They reported a reduction in opioid requirement and adverse effects. Ketamine in a multimodal regimen lower pain scores on coughing.
of PCEA has been shown to reduce analgesic re- The adverse effects of clonidine are dose related.
quirement after major surgery.[47,112] Wong et al.[114] When tested in healthy volunteers in a dose of demonstrated that the addition of ketamine to 700µg epidurally, Eisenach et al.[120] found that epidural morphine potentiates the analgesic effect of clonidine significantly reduced pain induced by ice morphine in patients undergoing total knee replace- water immersion, decreased plasma noradrenaline ment. Similarly, Chia et al.[47] showed that coadmin- levels and caused haemodynamic changes, but re- istration of a small dose of ketamine 0.4 mg/mL sulted in intense sedation that lasted up to 6 hours.
with a multimodal regimen (morphine, bupivacaine Dexmedetomidine has also been used for seda- and adrenaline) via PCEA provides better pain relief tion in intensive care[121] and as an analgesic adjunct at rest, during coughing or movement, and a reduc- during the intraoperative period. It has been demon- tion in analgesic consumption compared with PCEA strated to provide an opioid-sparing effect with min- alone. Recently, transdermal ketamine has been imal adverse effects.[122,123]  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) 2007 Adis Data Information BV. All rights reserved.
Table II. Studies on perioperative use of ketamine (KET)
Regimen (no. of patients) [duration of Pain scores vs control Analgesic consumption vs Bolus KET 0.5 mg/kg followed by infusion ↓ VAS (no significant ↓ morphine consumption No difference between 3 µg/kg/min intraop and 1.5 µg/kg/min difference between postop (n = 20); placebo using similar groups); early knee regimen with saline (n = 20) [48h] mobilisation better Reeves et al.[102] PCA morphine 1 mg/mL (n = 35); PCA No difference between No difference between Cognitive impairment morphine 1 mg/mL plus KET 1 mg/mL (p < 0.037) in KET group with vivid dreaming Surgical patients/GA Postop patients; IV morphine 30 µg/kg ↓ VAS at 10 and 120 ↓ morphine consumption Drowsiness (p < 0.001), plus saline (n = 114); IV morphine 15 µg/ min (p < 0.001) oxygen desaturation kg plus IV KET 250 µg/kg (n = 131) [2h] (p < 0.001) and PONV (p < 0.001) common in De Kock et al.[33] Placebo; IV KET bolus 0.25 mg/kg ↓ VAS in KET group 2 ↓ morphine consumption in No difference between followed by 0.125 mg/kg/h (group 1); IV IV KET group 2 (p < 0.05) combined epidural/ KET bolus 0.5 mg/kg followed by 0.25 mg/ kg/h (group 2); epidural KET 0.25 mg/kg followed by 0.125 mg/kg/h (group 3); epidural KET 0.5 mg/kg followed by 0.25 mg/kg/h (group 4) (n = 20 per group) [72h] KET 100 µg/kg bolus preop plus 2 µg/kg/ ↓ VAS (p = 0.01) ↓ morphine consumption No difference between min intraop followed by PCA morphine 1mg plus KET 0.5mg per bolus (n = 14); placebo (n = 14) [48h] Preincision (n = 45) or post skin closure ↓ VAS in preincision ↓ morphine consumption in No difference between (n = 45) KET 0.15 mg/kg; IV saline KET group (p = 0.001) preincision KET group Major pelvic surgery/ IV KET 0.5 mg/kg preincisional plus ↓ VAS over 6h postop ↓ analgesic need up to 24h No difference between CNS Drugs 2007; 21 (3) placebo (n = 15); IV KET 0.5 mg/kg in pre- and intraop in pre- and intraop group postop EA with LA preincisional plus 0.2 mg/kg repeated intraop (n = 15); placebo (n = 15) [6h] Pyati & Gan Continued next page Perioperative Pain Management 2007 Adis Data Information BV. All rights reserved.
Table II. Contd
Regimen (no. of patients) [duration of Pain scores vs control Analgesic consumption vs IV KET 0.15 mg/kg (n = 25) or placebo ↓ VAS up to 72h ↓ analgesic consumption No difference between (n = 25) at induction [3 days] Intrathoracic and PCEA morphine 0.02 mg/mL, bupivacaine ↓ VAS (p < 0.05) ↓ analgesic consumption No difference between 0.8 mg/mL and KET 0.4 mg/mL (n = 45); up to 48h (p < 0.05) placebo (n = 46) [3 days] Preincision epidural morphine alone (group ↓ morphine consumption in No difference between 1; n = 24); epidural KET plus morphine group 2 (p = 0.018), time for (group 2; n = 26) [48h] first analgesia request was prolonged in group 2 (p = 0.021); supplemental epidural morphine doses were similar in both groups Renal surgery/GA/ IV KET 0.5 mg/kg bolus followed by 0.5 ↓ VAS in KET group ↓ PCEA doses in KET mg/kg/h KET intraop (n = 20); placebo for 48h (p < 0.01) group for 48h (p = 0.001) common in control group Dreams/diplopia no difference between Gastrectomy (pre- Epidural morphine (group 1; n = 30); IV ↓ VAS in group 1 ↓ morphine consumption in emptive analgesia) KET plus epidural saline (group 2; n = 29); group 2 (p < 0.05) and IV KET plus epidural morphine (group 3; ↓ VAS in group 2 lowest in group 3 n = 31); IV saline plus epidural saline (group 4; n = 31) [48h] ↓ VAS in group 3(p < 0.005) PCEA morphine (group 1; n = 30); PCEA ↓ VAS in group 2 for ↓ morphine consumption up Vomiting common in morphine plus ketamine (group 2; n = 30) 3h postop (p < 0.05) to 24h in group 2 (p < 0.05) group 1 (p < 0.05); and no difference sedation, pruritus and CNS Drugs 2007; 21 (3) between groups during pyschomimetic effects 3–24h (p < 0.05) were not different EA = epidural anaesthesia; FNB = femoral nerve block; GA = general anaesthesia; intraop = intraoperative; IV = intravenous; LA = local anaesthetic; PCA = patient-controlled
analgesia; PCEA = patient-controlled epidural analgesia; PONV = postoperative nausea and vomiting; postop = postoperative; preop = preoperative; VAS = visual analogue scale
score; ↓ indicates reduction.
Pyati & Gan 3.7 Epidural Analgesia 3.8 Wound Infiltration withLocal Anaesthetics Epidural analgesia provides superior pain relief Infiltration of the surgical wound with local and attenuates the stress response to surgery and anaesthetics is commonly performed to achieve pain, particularly when used in the form of continu- wound analgesia. This method has been shown to be ous infusion both during and after surgery. Howev- effective in providing analgesia in trials where pa- er, clinical opinion remains divided regarding the tients have undergone inguinal hernia repair, al- benefits of epidural analgesia despite several studies though there is lack of evidence for any clinically demonstrating benefits such as greater patient satis- useful effect for most other abdominal procedures faction, less postoperative morbidity and improved (see review by Moiniche et al.[140]). Inadequate clinical outcome.[55,59,124-133] The results of some of doses of local anaesthetics may explain the poor the more recent studies, meta-analyses and reviews results in some trials. Wound infiltration does not are summarised in table III. A recent meta-analysis provide a beneficial effect on pulmonary function confirmed the value of epidural analgesia in reduc- after surgery.[129] ing cardiac, pulmonary, thromboembolic and renal The role of adjuvants to local anaesthetics is complications, in addition to providing superior unclear. For example, wound infiltration with bupivacaine and ketamine has not been shown to Combined use of epidural local anaesthetics and decrease pain score or the need for rescue analgesia, adjuvants not only provides intraoperative analgesia but the duration of analgesia has been reported to be but can also control postoperative pain effectively prolonged by the addition of ketamine.[141] The rou- after major thoracic, abdominal and lower limb sur- tine use of adjuvants in wound infiltration is current- geries.[135] Using adjuvants in the epidural space ly not recommended.
reduces the total dose of local anaesthetic. In chil-dren, several adjuvants have been used in caudal 3.9 Intra-Articular Analgesics blocks, including ketamine and clonidine, for pro- There are conflicting reports about the efficacy longation of analgesia after common paediatric op- of intra-articular analgesics.[142-144] Intra-articular NSAIDs when used alone are unlikely to exert any A study conducted in patients undergoing major clinically useful analgesic effect, but NSAIDs in intra-abdominal surgery demonstrated better pain combination with local anaesthetics may provide relief and reduced postoperative analgesic consump- prolonged analgesia.[145] Many orthopaedic sur- tion with epidural analgesia.[133] For hip and knee geons use intra-articular local anaesthetics follow- replacements, epidural anaesthesia with sedation ing arthroscopic surgery. In a systematic review, during surgery followed by postoperative epidural Moiniche et al.[146] observed that the use of intra- infusion of a combination of local anaesthetics and articular local anaesthetics seemed to provide mod- opioids has been used.[137] Lee et al.[138] demonstrat- erate pain relief of short duration. Although the pain ed a clear advantage of the combination of epidural relief in the early postoperative period was statisti- bupivacaine and diamorphine for analgesia after cally significant, evidence was not overwhelming in major gynaecological surgery. The combination favour of intra-articular local anaesthetics because provided superior pain relief with fewer adverse the majority of the studies did not demonstrate im- proved pain relief beyond the immediate postopera- Nonetheless, there are problems associated with tive period.
the continuous epidural technique such as hypoten- Peripheral anti-nociceptive actions of opioids sion, motor blockade and incompatibility with an- have been reported,[147] and thus opioids appear to ticoagulation. In addition, the failure rate with be effective in pain control when administered intra- epidural analgesia is approximately 30%.[139] articularly. Stein[148] showed that morphine exerts its  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management 2007 Adis Data Information BV. All rights reserved.
Table III. Studies on epidural analgesia in the perioperative period
Key findings in EA group RCT (MASTER Trial) 915 patients; 255 in ↓ incidence of respiratory failure (23% vs No difference in mortality surgery in high-risk epidural group, 268 in 30%) [p = 0.02], ↓ pain scores in epidural between groups; EA does not group on day 1 after coughing decrease perioperative major adverse complications; supportswidespread use of EA foranalgesia Systematic review of 141 RCTs, 9559 patients ↓ mortality by a one-third; ↓ DVT, PE; Reduction in postop morbidity; ↓ transfusion; ↓ pneumonia; ↓ respiratory supports use of EA depression [all p < 0.001] Beattie et al.[128] 11 RCTs, 1173 patients ↓ pain scores for 24h (p-value not No difference in mortality reported); ↓ postop MI especially with thoracic epidural (p = 0.04) ↓ mortality (p = 0.74) and major Overall no significant difference GA plus parenteral abdominal surgery complications in abdominal aortic surgery in morbidity/mortality up to 30 opioids/EA plus light (22% vs 37%); MI (p = 0.21), stroke days between groups; EA (p = 0.98), respiratory failure (p = 0.06) provides better pain relief; ↓ concurrent analgesic consumption supports use in AAA surgery Peyton et al.[59] Subgroup analysis of Subgroup of 915 patients No difference between groups in patients No evidence to support reduction at risk of respiratory, cardiac complications in mortality or morbidity with EA or aortic surgery; no difference in durationof hospital stay Systematic review ↓ pain scores with EA vs opioids Supports use of EA patients not reported) (p < 0.001); ↓ nausea, vomiting (p = 0.61) parenteral opioids and pruritus (p < 0.001) All types surgery 200–250 patients ↓ pulmonary infection (95% CI 0.21, 0.65); EA decreases pulmonary ↑ PaO2 (95% CI 0.058, 9.075); no difference in FEV1/FVC/ PEFR Cochrane systematic 13 studies, 639 patients Short-term ↓ in pain scores (4–6h) postop Supports use of EA for short- (95% CI –1.24, –0.31); ↓ in pain scores term pain relief; insufficient data (lumbar epidural vs on movement (p-value not reported); no to show ↓ in hospital stay, systemic analgesia) difference in PONV and respiratory morbidity and mortality due to EA depression; more frequent itching,retention of urine (95% CI 1.63, 7.51)and hypotension (95% CI –1.15, –6.72) Cochrane systematic 1224 patients; EA in 597 ↓ pain score; ↓ duration of postop Supports use of EA for pain relief patients, systemic opioids ventilation (p = 0.048); ↓ postop morbidity up to third postop day; no difference in postop mortality CNS Drugs 2007; 21 (3) Cochrane systematic Abdominal surgery ↓ pain scores in EA group during 72h EA superior to PCA. No review (continuous EA (WMD 0.63; 95% CI 0.24, 1.01); pruritus in difference in hospital stay Charuluxanum[134] vs opioid PCA) PCA group (OR 0.27; 95% CI 0.11, 0.64) AAA = abdominal aortic aneurysm; DVT = deep vein thrombosis; EA = epidural analgesia; FEV1 = forced expiratory volume in 1 second; FVC = forced vital capacity; GA = general
anaesthesia; MI = myocardial infarction; OR = odds ratio; PaO2 = partial pressure of oxygen; PCA = patient-controlled analgesia; PE = pulmonary embolism; PEFR = peak
expiratory flow rate; PONV = postoperative nausea and vomiting; postop = postoperative; RCT = randomised controlled trial; SA = spinal anaesthesia; WMD = weighted mean
difference; ↓ indicates reduction; ↑ indicates increase.
Pyati & Gan effect on peripheral opioid receptors when injected stimulating catheters has made placement of in- intra-articularly; however, a systemic effect cannot dwelling catheters safer and accurate.
be excluded. Gupta et al.,[149] in a meta-analysis, Continuous infusion of local anaesthetics evaluated 27 studies where intra-articular morphine through a peripheral nerve catheter is becoming was directly compared with placebo. In 13 of the increasingly popular in both hospital and ambulato- studies, intra-articular morphine had a mild benefi- ry settings to achieve prolonged analgesia.[155,156] cial effect (mean reduction in pain intensity, For example, continuous femoral nerve block has 12–17mm on a visual analogue score). Several stud- been shown to reduce the duration of hospital stay ies reported a reduction in analgesic requirement in and the frequency of serious complications after the morphine group. The efficacy of morphine de- total knee arthroscopy.[157] Similarly, several other pends on the dose used. A higher dose (5mg) inject- studies have demonstrated the benefits of peripheral ed intra-articularly is likely to provide analgesia nerve blocks (PNBs), including reduced duration of during the first 24 hours after surgery, whereas stay and costs,[155] decreased incidence of postopera- lower doses are ineffective.
tive nausea and vomiting,[158] and lower rates of Romsing et al.[94] in a systemic review highlight- unexpected hospital admissions after ambulatorysurgery.[155,157,159] ed four studies that compared intra-articular ketoro-lac 60mg or tenoxicam 20mg with systemic (intra- In a recent meta-analysis involving over 600 venous) administration. In two of these ketorolac patients, PNBs provided superior postoperative an- reports intra-articular bupivacaine was added in algesia when compared with administration of oral both groups.[145,150] All four studies showed signifi- and systemic opioids alone.[160] Patients who re- cantly lower pain scores after intra-articular admin- ceived perineural blocks with local anaesthetic also istration compared with systemic administration of demonstrated a significant reduction in opioid con- NSAIDs. In the intra-articular groups, time to first sumption, fewer opioid-related adverse effects and analgesic request was significantly increased post- better patient satisfaction. Of the six studies that evaluated clonidine,[161] five found improvement inanalgesia.
Data also suggest that using a combination of Evidence that the addition of peripherally admin- analgesics intra-articularly has beneficial effects.
istered opioids during PNB[162,163] improves the Patients who received intra-articular ketorolac in quality of either intraoperative regional anaesthesia addition to morphine demonstrated significantly or postoperative analgesia has not been established, lower pain scores compared with patients receiving with mixed results from different trials. Five trials either drug alone postoperatively.[151] Similarly, a measuring postoperative efficacy reported a signifi- combination of clonidine and neostigmine[152,153] cant difference in favour of the opioid;[162] however, have also been shown to exhibit peripheral analgesic the authors did not consider the findings important effects when used intra-articularly after knee ar- enough to advocate routine use of opioids in the throscopy. At a dose of 150µg intra-articularly, acute setting.
clonidine exerted analgesia comparable to morphinebut the combination of both did not provide pro- 3.11 Pre-Emptive Analgesia longed analgesia.[154] With a greater understanding of acute pain mech- 3.10 Peripheral Nerve Blocks anisms, it is known that tissue injury initiates periph-eral and central neuronal sensitisation, resulting in Appropriate nerve blocks, depending on the site perpetuation of the ‘pain state'.[164-166] Pre-emptive of surgery, are useful in providing short-term pain analgesia is analgesia given before the initiation of relief post-operatively. Direct visualisation of neural nociceptive stimulus. Several clinical studies tissue with ultrasound technology and the utility of hypothesised that preoperative administration of  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management analgesics or regional blockade would prevent or Numerous studies have demonstrated the effica- result in less postoperative pain[106,167-170] by protect- cy of gabapentin, and another GABA analogue pre- ing the nervous system from sensitisation. However, gabalin, as non-opioid analgesic adjuvants in post- the effectiveness of pre-emptive analgesia in routine operative pain management.[50,186-196] Table IV sum- clinical practice is debatable.[171,172] For pre-emptive marises some of these studies.
analgesia to be clinically important the duration of In a randomised study using single-dose analgesia obtained should be longer and with a gabapentin (1200mg) versus placebo, Dirks et al.[192] minimal increase in adverse effects, and the pre- found that there was a substantial reduction in mor- emptive intervention should have an effect on acute phine consumption after mastectomy in the postoperative pain or in preventing the development gabapentin group (total morphine consumption, of chronic pain.
29mg in the placebo group versus 15mg in the A recent review of the literature found that gabapentin group). In addition, pain scores were around 40% of studies demonstrated a beneficial lower in the treatment group in the early postopera- effect (reduction in pain and analgesic consumption) tive period. Dierking et al.[193] also demonstrated a of pre-incision (pre-emptive) analgesia as opposed reduction in morphine consumption (by 32%) when to analgesic administration after surgical incision gabapentin (3000mg) was administered before and (preventive).[173] Therefore, along with other factors during the first 24 hours after abdominal hysterecto- (drug, dose and duration) it appears that the timing my. A recent meta-analysis confirmed that gabapen- of analgesic initiation in relation to surgical incision tin in doses <1200mg has an analgesic and opioid- affects postoperative analgesic requirement when sparing effect in acute postoperative pain manage- analgesic activity of the agent has worn off.[174,175] ment when used in conjunction with opioids; how- The timing of administration of an agent may be pre- ever, it was associated with an increased risk of incision,[176] during surgery[177] or in the postopera- sedation but reduced opioid-related adverse effects tive period.[178] such as vomiting.[194] In a multi-modal approach, NMDA antagonists,[172] NSAIDs,[179] epidural Gilron et al.[195] reported that the combination of analgesia[180] and local anaesthetic infiltra- gabapentin and rofecoxib is superior to either agent tion[170,181,182] have all been used in pre-emptive alone after abdominal hysterectomy. With all pa- analgesia, with variable results.
tients receiving intravenous PCA, the gabapentin-rofecoxib combination (1800/50mg) demonstrated a 4. Novel Analgesic Therapy
significant reduction in morphine consumption,from 130mg in the placebo group to 57mg in thecombination group.
Based on the current evidence it appears that Gabapentin, which primarily has anticonvulsant gabapentin reduces supplementary postoperative an- properties, is used extensively in the treatment of algesic requirement. The optimal dose ratio devoid neuropathic pain. Despite its structural similarity to of adverse effects needs to be identified when GABA, gabapentin does not bind to GABA recep- gabapentin is used alone or in combination.
tors.[183] It has high affinity for α2-δ subunits ofvoltage-dependent calcium channels, resulting in 4.2 Corticosteroids postsynaptic inhibition of calcium influx and there-by reducing presynaptic excitatory neurotransmitter Corticosteroids have been used as anti-inflam- release.[184] It has been suggested that gabapentin is matory and anti-immunological agents for manifes- useful in reducing the central neuronal sensitisation tations of many autoimmune disorders. Corticoste- that occurs in postoperative pain, and postsurgical roids act by suppressing arachidonic acid production pain has been regarded by some as transient neuro- through lipocortin-induced phospholipase inhibi- pathic pain.[185] tion, which ultimately inhibits production of both  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) 2007 Adis Data Information BV. All rights reserved.
Table IV. Studies on perioperative use of gabapentin (GAB) and pregabalin (PGB)
Regimens (no. of patients) Pain scores vs control Analgesic consumption vs [duration of study] Dirks et al.[192] GAB 1200mg 1h preop (31); ↓ VAS on movement at 2h ↓ morphine consumption No difference between (p < 0.0001) and 4h Fassoulaki et al.[197] GAB 1200 mg/day for 10 days VAS rest and movement ↓ 50% ↓ codeine and No difference between (n = 22); mexiletine 600 mg/ by both drugs on day 3 paracetamol use days day for 10 days (21); PL for (p = 0.001); VAS on 2–10 (p = 0.003) 10 days (34) [3mo] movement ↓ by GAB days2–5 (p = 0.001) Turan et al.[190] GAB 1200mg 1h preop (25); ↓ VAS at 1, 2 and 4h ↓ morphine consumption Vomiting and urinary PL 1h preop (25) [24h] retention lower in GABgroup (p < 0.05) Dierking et al.[193] GAB 1200mg 1h preop No difference between followed by 600mg at 6, 8 and consumption (p < 0.001) 24h after first dose (39); PL 1hpreop followed by PL at 6, 8and 24h after first dose (32)[24h] Turan et al.[188] GAB 1200mg 1h preop (25); ↓ VAS up to 20h (p < 0.02) ↓ tramadol consumption No difference between PL 1h preop (25) [24h] Pandey et al.[187] GAB 300mg 2h preop (153); ↓ VAS compared with ↓ fentanyl consumption Sedation and PONV higher tramadol 100mg 2h preop tramadol (except 0–6h) vs tramadol and placebo in GAB group (p < 0.05) (153); PL 2h preop (153) [24h] and PL (p < 0.05) Rorarius et al.[189] GAB 1200mg 2.5h preop (38); Trend towards ↓ VAS in Trend towards less PONV oxazepam 15mg 2.5h preop consumption (p < 0.005) Turan et al.[191] ENT surgery under GAB 1200mg 1h preop (25); ↓ VAS postop (p < 0.001) ↓ intraop fentanyl use More dizziness in the GAB PL 1h preop (25) [24h] and at 45 and 60 min intraop (p < 0.05) and postop (24%) versus the PL group diclofenac use (p < 0.0010; (4%, p < 0.05) prolonged time to firstrescue analgesia(p < 0.001) Gilron et al.[195] GAB 1800mg 1h preop (25); ↓ VAS at rest (p < 0.05 vs ↓ morphine consumption Sedation more frequent rofecoxib 50mg 1h preop (30); all treatments) and on cough in GAB/rofecoxib group CNS Drugs 2007; 21 (3) GAB/rofecoxib 1800/50mg (p < 0.05 vs all treatments) (p < 0.05) [p <0.05 vs combination 1h preop (28); in GAB/rofecoxib group PL 1h preop (27) [72h] Pyati & Gan Continued next page Perioperative Pain Management prostaglandins and leukotrienes.[198] Corticosteroidsalso prevent the production of cytokines, which playa role in the mechanism of inflammatory pain. Atthe spinal level, corticosteroids exert anti-nocicep- tive effects.[199] Despite evidence for analgesic actions of cortico- steroids, there has not been widespread clinical use Higher incidence of dizziness in GAB group (p < 0.05) Sedation risk increased with higher doses Combination superior to = weighted mean difference; of these agents for the management of postoperative pain. This may be due to the adverse effects ofcorticosteroids when given in repeated doses forlonger periods postoperatively; however, most stud-ies have reported their analgesic effect after single doses. Several clinical investigations have evaluated the effect of systemic corticosteroids on pain aftersurgical procedures, demonstrating effective pain Analgesic consumption vs ↓ PCEA bolus requirements (p < 0.05); ↓ paracetamol consumption (p < 0.05) ↓ opioid consumption (WMD = ↓ 24h morphine consumption in combined group (p < 0.01) relief and early recovery.[200-202] In a double-blind, = patient-controlled epidural analgesia; placebo-controlled, single-dose, randomised study, = visual analogue scale score; Romundstad et al.[203] compared intravenous ketoro- lac with intravenous methylprednisolone 125mg inpatients with moderate to severe pain one day afterorthopaedic surgery. They demonstrated that thepain intensity in the corticosteroid group was signif-icantly lower up to 6 hours postoperatively com-pared with placebo, and similar to ketorolac. Opioid Pain scores vs control ↓ VAS in GAB group (p < 0.001) ↓ VAS (WMD = 16.55 at 6h and 10.87 at 24h for single dose). Multiple dosing does not reduce pain scores ↓ VAS in combination group (p < 0.05) over 24h period consumption in the first 72 hours was significantly = monitored anaesthesia care; lower in the methylprednisolone group than in the = randomised controlled trial; ketorolac and placebo groups. No serious adverse effects were reported.
Glucocorticoids may have sustained analgesic effects after surgery; however, the disadvantage ofrepeated corticosteroid administration and adverse = intraoperative; effects in postoperative patients needs further inves- = postoperative; tigation in adequately powered trials.
Regimens (no. of patients) [duration of study] GAB 1200mg 1h preop (20); PL 1h preop (20) [72h] Systematic review: 16 RCTs (n = 1151; GAB = 614); varying doses of GAB Placebo preop/postop (n = 20); CLB preop 400mg/postop 200mg (n = 20); PGB preop 150mg/postop 150mg (n = 20); CLB/PGB preop 400/150mg, postop 200/150mg (n = 20) 4.3 Opioid Receptor Antagonists Naloxone and nalbuphine (a partial opioid recep- tor agonist) are used to treat neuropathic pain.[204] In = preoperative; vitro studies have demonstrated that a long-acting All types of surgery nalbuphine preparation had antinociceptive action = ear, nose and throat; for up to 55 hours.[205] Evidence from animal studies also illustrates that opioid antagonists enhance the potency of morphine and attenuate opioid toler- In one study, low-dose naloxone infusion in the Table IV.
Turan et al.
Reuben et al.
nausea and vomiting; ↓ indicates reduction.
postoperative period after gynaecological surgery  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Pyati & Gan was shown to reduce opioid-related adverse effects its serum concentrations are insignificant.[216] There and opioid requirements.[208] However, there is in- may be a potential role of topical lidocaine in acute conclusive evidence from several other clinical tri- postoperative pain but this needs further investiga- als on the effectiveness of opioid antagonists to attenuate postoperative pain and reduce opioid re-quirements.[209,210] In a recent randomised, double- 4.6 Patient-Controlled Transdermal Fentanyl blinded clinical study, Cepeda et al.[211] compared a Patient-controlled transdermal fentanyl offers a naloxone-morphine combination with morphine non-invasive opioid delivery system for acute pain alone in PCA. There was no difference in opioid management. Using iontophoresis technology, requirements and pain between the groups. The fentanyl 40µg is delivered on demand.[217] A multi- combination group experienced less nausea and pru- centre trial reported that patient-controlled trans- ritus than the morphine only group; however, nalox- dermal fentanyl was superior to placebo in control- one was unable to reduce the vomiting, sedation and ling moderate to severe pain up to 24 hours after urinary retention seen in the morphine only group.
major surgery.[218] 4.4 Magnesium Sulfate 5. Nonpharmacological Options
Recently, the role of magnesium sulfate as an Nonpharmacological therapy should be consid- NMDA receptor antagonist and as an adjuvant to ered as complimentary to pharmacological options analgesic therapy has been investigated. Intravenous for postoperative pain management. It provides ad- magnesium sulfate 50 mg/kg preoperatively fol- ditional benefit in reducing the total dose of lowed by an infusion postoperatively in patients analgesics required and therefore minimising the undergoing open cholecystectomy has been reported adverse effects of the analgesics.
to result in less discomfort than saline treatment,[212]although there was no effect on opioid requirement.
5.1 Transcutaneous Electrical In another study,[213] patients randomised to 20% Nerve Stimulation intravenous magnesium sulfate before surgeryshowed reductions in postoperative PCA morphine TENS has been used widely in chronic pain requirements in the first 48 hours compared with conditions. The evidence for its efficacy in acute patients receiving saline.
postoperative pain is inconclusive, mainly due to a Contrary to the above findings, in a systematic lack of well-conducted, randomised controlled tri- review examining the efficacy of NMDA antago- als. Many published studies have methodological nists, McCartney et al.[214] reported that none of the flaws. Blinding is difficult in trials associated with four studies examining magnesium to reduce post- TENS because patients easily notice the presence or operative pain and analgesic requirements demon- absence of paraesthesia; therefore, inadequate strated any evidence in favour of preventive analge- randomisation may exaggerate the efficacy by up to sia; in contrast, ketamine and dextromethorphan were effective in this regard.
A systematic review by Carroll et al.[220] demon- strated TENS to be no better than placebo in the 4.5 Lidocaine (Lignocaine) Patches treatment of acute postoperative pain. A wide varie- Lidocaine (lignocaine) provides analgesia by ty of procedures from hernia to thoracotomy were blocking the sodium neuronal channels locally and studied and ten different TENS units were used with thereby dampens peripheral nociceptor sensitisa- different control settings and duration of treatment.
tion. Transdermal lidocaine (5%) has been used to Fourteen trials compared TENS with sham TENS.
treat pain associated with post-herpetic neural- None found any difference between the two treat- gia.[215] When lidocaine is applied as a topical agent, ments. However, when TENS was compared with  2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Perioperative Pain Management opioids, one trial[221] reported significantly fewer pain scores at home on the day of surgery and up to pethidine injections and better pain scores on the 48 hours afterwards were low and there were no first postoperative day in patients receiving TENS.
significant differences between the three groups.
Previous systematic reviews[49,222] on TENS and This study suggests that music therapy has a short- postoperative pain showed several inconsistencies term benefit in reducing pain and anxiety, decreas- in the effectiveness of TENS. All available trials of ing the pain perception through cognitive cop- postoperative pain used TENS as an adjuvant to ing.[227] The type and duration of music therapy medication, and it is possible that the effect of TENS needed are still unclear. However, a recent systemat- was masked by the analgesic effect of the medica- ic review demonstrated a small reduction in pain scores and opioid consumption after music ther-apy.[228] 5.2 Relaxation Techniques Relaxation has become increasingly popular as an adjuvant to conventional analgesic therapy. It has Acupuncture, a form of traditional Chinese been suggested that it works by breaking the pain- medicine, has been a topic of interest in managing tension-pain cycle.[223] postoperative pain. Several studies of acupuncture Seers and Carroll[224] conducted a systematic re- have demonstrated an analgesic effect and a reduc- view to investigate the effectiveness of relaxation tion in the incidence of nausea and vomiting.[229,230] techniques when used alone in the management of The success of acupuncture as an adjuvant in bal- acute pain. Three of the seven studies they assessed anced analgesia depends on several factors, includ- demonstrated significantly less pain or pain distress ing the skills of the acupuncturist,[231] method of with relaxation. Most studies were poorly designed stimulation and duration of acupuncture therapy.
with a lack of adequate controls, and a variety of The mechanism by which acupuncture produces relaxation techniques was used. This meta-analysis analgesia is still unclear. The ‘gate control theory' proposed the need for better quality trials to estab- and secretion of endogenous opioids such as en- lish the efficacy of relaxation techniques for acute dorphins, encephalins and dynorphins may contrib- postoperative pain before it is widely accepted as a ute to acupuncture-induced analgesia.[232,233] routine analgesic intervention.
Kotani et al.[234] tested the effect of acupuncture 5.3 Music Therapy on postoperative pain in a controlled and double-blind study involving patients undergoing abdomi- Music therapy during and after surgery has been nal surgery. The investigators preoperatively insert- used as complimentary to other methods of pain ed intradermal needles at acupoints 2.5cm bilateral- management. Several studies claim benefit of music ly from the spinal vertebrae (bladder meridian). All therapy in reducing pain scores and anxiety.[225-227] these patients had an epidural catheter inserted for Nilsson et al.[226] in a controlled trial examined 151 abdominal surgery. The pain relief was significantly patients undergoing day case surgery for inguinal better in the treatment group than in the control hernia repair or varicose veins surgery under general group until the second postoperative day. The treat- anaesthesia. Patients who were exposed to music ment group required less morphine, by up to 50%. In intraoperatively or postoperatively reported lower contrast, Sim et al.[235] have shown that preoperative pain intensity in the early postoperative period than electro-acupuncture-induced analgesia did not re- a control group who were exposed to ‘white noise'.
duce 24-hour morphine requirements after gynaeco- It is interesting to note that the postoperative music logical lower abdominal surgery. This may be due to group required less morphine at 1 hour compared the short duration of action of electro-acupuncture with the control group in the recovery room. The when used during the preoperative period.
 2007 Adis Data Information BV. All rights reserved.
CNS Drugs 2007; 21 (3) Pyati & Gan paracetamol, NSAIDs, systemic opioids or continu-ous epidural analgesia with local anaesthetic and Numerous studies have demonstrated the effica- opioid combination should be considered. PNBs are cy of hypnosis for reducing pain in the laboratory likely to be more effective for limb surgeries. Evi- setting and case reports have indicated reductions in dence suggests that acute pain can trigger long-term clinical pain.[236-239] There is evidence to suggest that plastic neuronal changes leading to a chronic pain hypnosis may modify pain perception, at least to state. Drugs such as ketamine and gabapentin given some degree, through inhibition at the spinal level.
in the perioperative period may reduce the incidence In acute pain, there is a substantial amount of of chronic pain. Combination analgesics supple- anecdotal evidence and some controlled studies to mented by nonpharmacological therapy will contin- support the efficacy and use of hypnosis. Montgom- ue to play a vital role in the everyday comprehensive ery et al.[240] conducted a meta-analysis to estimate management of acute postoperative pain.
the effectiveness of adjunctive hypnosis in control-ling signs and symptoms after surgery. This meta- analysis suggested that an average 89% of surgical Dr Gan has received research support and honoraria from patients in hypnosis groups benefited relative to Merck, Ortho-McNeil and Pfizer. Dr Pyati has no conflicts of control patients. They also observed that the patients interest that are directly relevant to the contents of this in the treatment group reflected greater satisfaction review. No sources of funding were used to assist in the than the controls.
preparation of this review.
Evidence suggests that hypnosis is a useful tool to modulate pain and to alter a patient's perception 1. Dolin SJ, Cashman JN, Bland JM. Effectiveness of acute post- to change their expectations about pain;[241] howev- operative pain management: I. Evidence from published data.
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CNS Drugs 2007; 21 (3)


Le Journal du Patient N°18 Juin 2014 Panne sous la couette, comment remonter la pente? En Belgique, un homme sur 3 de plus de 40 ans souffre de troubles de l'érection. Il existe aujourd'hui des solutions efficaces mais les Belges sont encore trop peu nombreux à en profiter. Quelles sont les questions à se poser pour ouvrir le dialogue? Le Journal du Patient N°18 Juin 2014

Death by medicine by gary null, phd; carolyn dean md, nd; martin feldman, md; debora rasio, md; and dorothy smith, phd

Death by Medicine By Gary Null, PhD; Carolyn Dean MD, ND; Martin Feldman, MD; Debora Rasio, MD; and Dorothy Smith, PhD Something is wrong when regulatory agencies pretend that vitamins are dangerous, yet ignore published statistics showing that government-sanctioned medicine is the real hazard. Until now, Life Extension could cite only isolated statistics to make its case about the dangers of conventional medicine. No one had ever analyzed and combined ALL of the published literature dealing with injuries and deaths caused by government-protected medicine. That has now changed.

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