AUTHORS :-
DR. RAKESH SHAH,
PROFESSOR & P.G. GUIDE DEPT OF ORAL & MAXFACIAL SURGERY, K.M. SHAH DENTAL COLLEGE & HOSPITAL

Abstract

Pain, which is often inadequately treated, in our day to day practice.  Preemptive analgesia, an evolving clinical concept, involves the introduction of an analgesic regimen before the onset of noxious stimuli, with the goal of preventing sensitization of the nervous system to subsequent stimuli that could amplify pain. Surgery offers the most promising setting for preemptive analgesia because the timing of noxious stimuli is known.
When adequate drug doses are administered to appropriately selected patients before surgery, intravenous opiates, local anesthetic infiltration, nerve block, subarachnoid block and epidural block offer benefits that can be observed as long as one year after surgery. The most effective preemptive analgesic regimens are those that are capable of limiting sensitization of the nervous system throughout the entire perioperative period.

Introduction

Pain is thought to be inadequately treated in one half of all surgical procedures. In addition to immediate unpleasantness, painful experiences can imprint themselves indelibly on the nervous system (Figure 1), amplifying the response to subsequent noxious stimuli (hyperalgesia) and causing typically painless sensations to be experienced as pain (allodynia). A chronic condition sometimes develops that produces continuous pain long after surgery. Prior painful experiences are a known predictor of increased pain and analgesic use in subsequent surgery.1,2

Pain Response

Both the peripheral and the central nervous systems (CNS) are involved in the perception of pain, with the spinal and supraspinal components of the CNS playing key roles3 (Figure 2)4. The transduction of noxious stimuli begins with peripheral nociceptors. Signals from these nociceptors travel primarily along small myelinated A and unmyelinated C fibers with soma lying in the dorsal root ganglion. Their axons synapse in the dorsal horn of the spinal cord, where the neurons of laminae I, II and V are most involved in the perception of pain. The signals then travel along the spinothalamic tract of the spinal cord to the thalamus and the cortex. Large fiber inputs from other sensory modalities and descending pathways can modulate activity in the dorsal horn, where these descending pathways may provide a physiologic explanation for the increased pain experienced by patients who have high levels of depression and anxiety. Painful stimuli ultimately cause activity in both the somatotopically appropriate portion of the sensory cortex and the limbic system.

The response to noxious stimuli can be modulated by their repeated application. For example, peripheral nociceptors become more responsive with the repeated application of noxious stimuli. Their sensitivity can be further enhanced by many tissue factors and inflammatory mediators released in the course of tissue injury. The response of neurons in the dorsal horn of the spinal cord of experimental animals has been found to be biphasic. The initial response to a noxious stimulus is brief and correlates with the sharp, well-localized initial pain. The second phase of the response is more prolonged and correlates with the dull, diffuse pain experienced after the initial injury. Experimentally, this second phase is associated with a growing region of hypersensitivity around the point where the noxious stimulus was initially applied. The process through which the neurons of the dorsal horn of the spinal cord become sensitized by prior noxious stimuli is often referred to as “windup” or “central sensitization.” Much less is known about pain-induced sensitization of the supra spinal components of the CNS. Collectively, however, the above mechanisms enhance sensitivity to noxious stimuli and may increase the level of pain experienced following surgery.
Preemptive Analgesia One of the most critical observations concerning central sensitization is the role played by the first phase of the pain response. Opiates administered before the first phase and reversed with the opiate antagonist naloxone (Narcan) before the expected onset of the second phase were capable of preventing this late stage of the pain response.5

Thus, preventing the initial neural cascade could lead to long term benefits by eliminating the hypersensitivity produced by noxious stimuli. Animal experiments demonstrated the benefits of preventing central sensitization by infiltrating with local anesthetics,6 an approach that was particularly effective with pain associated with deafferentation, as might occur with amputation. Collectively, results like these led to the concept of preemptive analgesia—initiating an analgesic regimen before the onset of the noxious stimulus to prevent central sensitization and limit the subsequent pain experience.7,8
Surgery may be the clinical setting where preemptive analgesia techniques will be the most effective because the onset of the intense noxious stimulus is known (Figure 3).9

Strategies:- Preemptive analgesia strategies have involved interventions at one or more sites along the pain pathway (Figure 2)4. These strategies have included infiltration with local anesthetics10,11, nerve block,12 intravenous analgesics13 and anti-inflammatory drugs.14

Review of literature

Despite solid demonstrations of its effects in some animal models, considerable controversy surrounds the use of preemptive analgesia in clinical settings. This controversy exists because not all clinical trials of preemptive analgesia have resulted in clear demonstrations of its efficacy. In evaluating clinical trials of preemptive analgesia, the timing of the intervention is only one factor. It is also essential to consider the ability of the intervention to prevent central sensitization and whether other aspects of the peri-operative pain experience may be of sufficient duration and intensity to mask any intra-operative benefits from the preemptive analgesia.

Sisk et al15 in 1990 conducted a clinical trial for a comparison of preoperative and postoperative naproxen sodium for suppression of postoperative pain in dental surgery cases. In their trial they have given naproxen sodium 550 mg 30 min postop  in control group while in preemptive group naproxen sodium 550 mg po 30 min preop  given. Results are not supportive of use of preemptive analgesia.

Gordon et al16. in 1997 conducted concluded Blockade of peripheral neuronal barrage reduces postoperative Pain. In their trial they have injected NS in control group while in preemptive group local infiltration 0.5% bupivacaine given and patient is observed post-operatively for 48 hrs. Results are supportive of use of preemptive analgesia.

Ong et al17 in 2004 conducted a double blind, randomized, placebo-controlled study where 34 patients had each of their identical impacted mandibular third molars removed under local anaesthesia on two occasions. Each patients acted as their own control; one side was pre treated with intravenous ketorolac 30 mg before surgery followed by placebo injection after surgery, and for the other side, the patient was given placebo injection before surgery and post-treated with intravenous ketorolac 30 mg after surgery. The difference in postoperative pain between pre treated and post-treated side in each patient was assessed by four primary end-points: pain intensity as measured by a 100-mm visual analogue scale hourly for 12 h, time to rescue analgesic, postoperative analgesic consumption, and patient’s global assessment. Throughout the 12-h investigation period, patients reported significantly lower pain intensity scores in the ketorolac pre treated sides when compared with the post-treated sides Patients also reported a significantly longer time to rescue analgesic, lesser postoperative analgesic consumption

Ong et al18 (2004) conducted study, The objective of this study was to compare the analgesic efficacy of a single-dose of preoperative intravenous tramadol versus ketorolac in preventing pain after third molar surgery. Sixty-four patients undergoing elective third molar surgery were randomly assigned into one of the two groups (32 in each group): Group I received tramadol 50 mg, and Group 2 received ketorolac 30 mg intravenously preoperatively before the surgery. And concluded that Preoperative intravenous ketorolac 30 mg is more effective than tramadol 50 mg in the prevention of postoperative dental pain.
Ong et al19 in 2005 Seventy-two patients undergoing elective third molar surgery were randomized to receive either intravenous or oral tramadol 50 mg. The intravenous group received an oral placebo capsule followed by intravenous tramadol 50 mg preoperatively. The oral tramadol group received a 50-mg oral tramadol capsule followed by intravenous placebo saline preoperatively. Throughout the 8-hour investigation period, patients reported significantly lower pain intensity scores in the intravenous versus oral group. Patients also reported significantly longer time to rescue analgesic and lesser postoperative analgesic consumption came to the conclusion that preoperative intravenous tramadol is superior to oral tramadol for preventing postoperative pain following third molar surgery.

Pektas et al20 (2006) have conducted a prospective, randomized, single-blind, crossover study to compare the pre-emptive analgesic efficasy of diflunisal 1000 mg was compared with that of lornoxicam 16 mg in 40 ASA I patients undergoing surgical removal of bilateral impacted third molars. The impacted third molar teeth on one side were removed at the first surgical appointment using one of the two drug regimens being assessed and the teeth on the contra lateral side were removed at a second appointment using the alternate drug regimen and concluded that Pre-emptive administration of both NSAIDs proved to be effective in the management of pain following the surgical removal of impacted third molar teeth.
Aoki et al21 in 2006 compare the efficacy of the selective cyclooxygenase-2 (COX-2) inhibitor meloxicam for treatment of postoperative oral surgical pain was assessed in a randomized controlled trial. Patients undergoing unilateral mandibular 3rd molar extraction surgery were allocated to 3 groups, A, B and C. After oral premedication of meloxicam 10 mg in group A, ampiroxicam 27 mg in group B and placebo in group C, surgery was completed within 30 min under local anaesthesia using 2% lidocaine. For postoperative pain relief the patients were allowed to take oral loxoprofen (60 mg per tablet). Postoperative pain was evaluated at the clinic on the 1st, 7th and 14th postoperative day (POD) using a visual analogue scale (VAS) and concluded that COX-2 inhibitor, meloxicam 10 mg used for premedication reduced postoperative pain compared with control in oral surgery.

Amaury et al22 in 2007 compared the efficacy of tramadol given before or immediately after surgical extraction of an impacted mandibular third molar under local anaesthesia. In this prospective, randomized, controlled, double-blind pilot study, 3 groups of 20 patients each were included: tramadol preoperative, 100 mg intramuscularly (IM) 1 hour before surgery (group A); tramadol postoperative, 100 mg IM immediately after surgery (group B); and saline (group C). This study suggests the preemptive use of tramadol as an alternative for the acute pain treatment after the removal of an impacted mandibular third molar carried out under local anaesthesia.

A.M. Tüzüner-Öncül et al23 in 2009 conducted study to compare the postoperative analgesic affects of preemptive intravenous paracetamol (perfalgan) and two different non-steroidal anti-inflammatory drugs intramuscular diclofenac sodium and intravenous lornoxicam for postoperative pain in patients undergoing impacted third molar surgery. 60 impacted third molar patients who underwent surgical removal of an impacted third molar requiring bone removal were randomly allocated into three groups. Coming to the conclusion that Preoperative intramuscular diclofenac, intravenous paracetamol and lornoxicam effectively decrease the postoperative flurbiprofen consumption and lower the postoperative pain intensity.

Kaczmarzyk n et al24. in 2010 conducted A prospective, randomized, double-blinded clinical trial   Preemptive effect of ketoprofen on postoperative pain following third molar surgery. The 96 patients were placed into three groups: pre-group (ketoprofen 60 min preoperatively); post-group (ketoprofen 60 min postoperatively); and no-group (placebo). And comes to the result that initial onset of pain was significantly delayed only in the post-group. Pain intensity at the first onset of pain was significantly lower only in the post-group. Patients in the pre- and postgroups required significantly less rescue analgesic than those in the no-group. Ketoprofen administered after third molar surgery provides more effective pain control than ketoprofen administered before the surgery or placebo.
Discussion

The emphasis should not be solely on the timing of treatment initiation, but on the pathophysiologic phenomenon it is intended to prevent altered sensory processing. The underlying principle is that the therapeutic intervention be made prior to the onset of pain, rather than as a reaction to it. The preemptive treatment should provide analgesia throughout the period of noxious stimulation that induces the altered sensory processing (central hyper excitability). Inflammatory reactions to tissue damaged during surgery (secondary phase of injury) may provide a source of sensory signalling postoperatively, and can induce central sensitization, even if it were initially prevented from occurring intra operatively.

Thus, the process by which the nervous system becomes sensitized by noxious stimuli offers both an explanation for the pain that persists after a traumatic experience, and a means for reducing the short-term and long term painful effects of such stimuli. The available studies indicate that modest short-term interventions are not likely to provide meaningful benefits in the face of massive tissue injury.

The antinociceptive treatment should completely block the noxious signals to the CNS, or else central sensitization may occur in response to those nociceptive impulses, which break through the analgesic barrier. Furthermore, total blockade of nociceptive afferent fibres may not be produced by conventional analgesic doses or methods. The aim of treatment is to minimize patient discomfort, while leaving physiologic nociceptive mechanisms intact so that they continue to function as an early warning system. An analgesic plan must include consideration of the best route of delivering analgesia (oral, iv, epidural, intra thecal or infiltration), the potential intensity of the noxious stimuli, the temporal relationship of nociceptive impulses to the timing and duration of surgery, the duration of the postoperative pain state, and the analgesic agents suitable for administration in each individual case. Different treatment regimes can be used at different times relative to surgery to maximize the prevention of pain in response to different levels of sensory input.

Conclusion :

Preemptive analgesia is not a new concept, but dates to the early twentieth century. It involves delivery of analgesic therapy that precedes, adequately blocks, and outlasts the nociceptive stimuli that accompany tissue injury. The aim is to prevent the peripheral and central sensitization that occurs in response to painful stimuli, while leaving physiological pain responses intact. Such an effect reduces primary and secondary hyperalgesia, allodynia and the receptive field changes of dorsal horn cells. While opioids, NSAIDs, local anaesthetics, alpha-2 agonists and NMDA receptor antagonists are considered the main agents in the preemptive analgesic arsenal, a variety of other potentially beneficial agents are under investigation. Until further data are complete, the presently available analgesics administered correctly (on time, for the appropriate duration, and in the proper dosage and manner) can improve patient comfort, decrease postoperative morbidity and have the potential to effect health care savings.

REFERENCES

1. Bachiocco V, Scesi M, Morselli AM, Carli G. Individual pain history and familial pain tolerance models: relationships to post-surgical pain. Clin J Pain 1993;9:266-71.
2. Taenzer P, Melzack R, Jeans ME. Influence of psychological factors on postoperative pain, mood and analgesic requirements. Pain 1986;24:331-42.
3. Fields HL. Pain. New York: McGraw-Hill, 1987.
4. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993;77:1048-56.
5. Dickenson AH, Sullivan AF. Subcutaneous formalininduced activity of dorsal horn neurons in the rat: differential response to an intrathecal opiate administered pre or post formalin. Pain 1987;30:349-60.
6. Coderre TJ, Vaccarino AL, Melzack R. Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Res 1990;535:155-8.
7. Gonzalez-Darder JM, Barbera J, Abellan MJ. Effects of prior anaesthesia on autotomy following sciatic transection in rats. Pain 1986;24:87-91.
8. McQuay HJ. Pre-emptive analgesia [Editorial]. Br J Anaesth 1992;69:1-3.
9. Woolf CJ, Chong MS. Preemptive analgesia—treating postoperative pain by preventing the establishment of central sensitization. Anesth Analg 1993;77:362-79.
10. Tverskoy M, Cozacov C, Ayache M, Bradley EL, Kissin I. Postoperative pain after inguinal herniorrhaphy with different types of anesthesia. Anesth Analg 1990;70:29-35.
11. Ke RW, Portera G, Bagous W, Lincoln SR. A randomized, double-blinded trial of preemptive analgesia in laparoscopy. Obstet Gynecol 1998;92:972-5.
12. Bugedo GJ, Carcamo CR, Mertens RA, Dagnino JA, Munoz HR. Preoperative percutaneous ilioinguinal and iliohypogastric nerve block with 0.5% bupivacaine for post-herniorrhaphy pain management in adults. Reg Anesth 1990;15:130-3.
13. Tverskoy M, Oz Y, Isakson A, Finger J, Bradley EL, Kissin I. Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994;78:205-9.
14. Souter AJ, Fredman B, White PF. Controversies in the perioperative use of nonsteroidal anti-inflammatory drugs. Anesth Analg 1994;79:1178-90.
15. Sisk AL, Grover BJ.A comparison of preoperative and postoperative naproxen sodium for suppression of postoperative pain. J Oral Maxillofac Surg 1990; 48:674–8.
16. Gordon SM, Dionne RA, Brahim J, Jabir F, Dubner R. Blockade of peripheral neuronal barrage reduces postoperative pain. Pain 1997; 70: 209–15.
17. Ong KS, Seymour RA, Chen FG. Preoperative ketorolac has a preemptive effect for postoperative third molar surgical pain Int. J. Oral Maxillofac. Surg. 2004; 33: 771–776
18. Ong KS, Tan JM: Preoperative intravenous tramadol versus ketorolac for preventing postoperative pain after third molar surgery. Int. J. Oral Maxillofac. Surg. 2004; 33: 274–278.

19. Ong KS, Lirk P, Juliana MH, Belle WY. Sow. The Analgesic Efficacy of Intravenous Versus Oral Tramadol for Preventing Postoperative Pain After Third Molar Surgery. J Oral Maxillofac Surg.2005;63:1162-1168

20. Pektas ZO, Sener M, Bayram B, Eroglu T, Bozdogan N, Donmez A, Arslan G, Uckan S: A comparison of pre-emptive analgesic efficacy of diflunisal and lornoxicam for postoperative pain management: a prospective, randomized, single-blind, crossover study. Int. J. Oral Maxillofac. Surg. 2007; 36: 123–127.

21. Aoki T, Yamaguchi H, Naito H, Shiiki K, Izawa K, Ota Y, Sakamoto H, Kaneko A: Premedication with cyclooxygenase-2 inhibitor meloxicam reduced postoperative pain in patients after oral surgery. Int. J. Oral Maxillofac. Surg. 2006; 35: 613–617.

22. Guillen AP,Ricardo MR, Patricia AB, Jose PU,
Pre-Emptive Analgesic Effect of Tramadol After Mandibular Third Molar Extraction: A Pilot Study J Oral Maxillofac Surg.2007;65:1315-1320

23. Tüzüner-Öncül AM,  Yazicioglu D, Alanoglu Z, Demiralp S, Öztürk A, Ucok C, Preemptive diclofenac sodium, paracetamol, lornoxicam for postoperative analgesia in third molar surgery. J Oral Maxillofac Surg.2009;03.550

24. Kaczmarzyk T, Wichlinski J, Stypulkowska J, Zaleska M, Woron J: Preemptive effect of ketoprofen on postoperative pain following third molar surgery. A prospective, randomized, double-blinded clinical trial. Int. J. Oral Maxillofac. Surg.2010; 7: 39:647-52.

Fig 1

Fig 2

Fig 3

Study	Control group	Type of analgesia in preemptive group	Type of surgery	Postop pain scores (preemptive group)	Duration of follow up	Supportive / non supportive of preemptive effect
Sisk et  al. 1990	naproxen sodium 550 mg po 30 min postop	naproxen sodium 550 mg po 30 min preop	dental surgery	N/A	N/A	not supportive
Peduto et al.(1995)		Ketorolac0.4 mg/kg	Nasal septoplasty			Supportive
Bridgman et al.(1996)	NS	Diclofenac, 100 mg oral	Third molar extractions			Supportive
Gordon et al. 1997	NS	local infiltration 0.5% bupivacaine	3r d molar tooth extraction	N/A	48	Supportive
Ong et al (2004)	intravenous ketorolac 30 mg after surgery	intravenous ketorolac 30 mg before surgery	mandibular third molar surgery		12 hrs	Supportive
Ong et al (2004)		intravenous ketorolac 30 mg and tramadol 50 mg	mandibular third molar surgery		12 hrs	Supportive intravenous ketorolac is batter then Tramadol
Selami et al ( 2006 )	physiological Saline via nebulizer	inhaled morphine via nebulizer	septoplasty andseptorhinoplasty		4 hrs	Supportive
Pektas et al (2006)		diflunisal and lornoxicam	mandibular third molar surgery		24 hrs	Supportive
Aoki et al (2006)	ampiroxicam 27 mg or plecebo post op	meloxicam 10 mg pre operatively	mandibular third molar surgery		14 days	Supportive
Amaury et al (2007)	tramadol postoperative 100 mg IM after surgery	tramadol preoperative 100 mg IM 1 hour before surgery	mandibular third molar surgery		24 hrs	Supportive
A.M. Tüzüner-Öncül et al(2009)		intravenous paracetamol, intramuscular diclofenac sodium and intravenous lornoxicam	Third molar extraction		48 hrs	Supportive
Kaczmarzyk n et al. (2010)	ketoprofen administered 60 min after surgery or placebo	ketoprofen 60 min preoperatively	Third molar extraction		12 hrs	not supportive