|Year : 2013 | Volume
| Issue : 3 | Page : 114-120
Pre-emptive analgesia: Recent trends and evidences
Amiya K Mishra, Mumtaz Afzal, Siddhartha S Mookerjee, Kasturi H Bandyopadhyay, Abhijit Paul
Department of Anaesthesiology, Perioperative care and Pain Services, Medica Superspeciality Hospital, Mukundapur, Kolkata, West Bengal, India
|Date of Web Publication||7-Jan-2014|
Department of Anaesthesiology Pain Medicine and Perioperative Care, Medica Superspeciality Hospitals, 127, Mukundapur, E. M. Bypass, Kolkata - 700 107, West Bengal
Source of Support: None, Conflict of Interest: None
Preemptive analgesia, initiated before the surgical procedure to prevent pain in the early postoperative period has the potential to be more effective than a similar analgesic treatment initiated after surgery. This article aims to review all the recent published evidences that assess the efficacy of this enigmatic concept. Materials and Methods: We reviewed original research articles, case-reports, meta-analyses, randomized control trials (RCTs), and reviews based on pain physiology for preemptive analgesia from Medline, Medscape, and PubMed from 1993 to 2013. A broad free-text search in English was undertaken with major keywords "Preemptive analgesia," "postoperative pain," "preoperative," and "preincisional". Results: Review of publications showed that intravenous (IV) nonsteroidal anti-inflammatory drugs (NSAIDs) are quite effective when used alone, as well as with low dose iv ketamine, preemptively to provide adequate postoperative analgesia. However, ketamine has a doubtful role as a standalone agent. Preemptive administration of LA at the incision site reduces postoperative pain, but achieves an analgesic effect similar to that of postincisional anesthetic infiltration as does intraperitoneal administration. Preemptive epidural analgesia has proved its efficacy in controlling perioperative immune function and pain in comparison to parenteral opioids. Gamma-amino butyric acid (GABA) analogues like gabapentin and pregabalin have great potential as preemptive analgesic with the added advantage of its anxiolytic effect. Conclusion: Multimodal approaches that address multiple sites along the pain pathway is necessary to treat pain adequately. However, we need to find an answer to the question of how to obtain the maximal clinical benefits with the use of preemptive analgesia.
Keywords: Central sensitization, preemptive analgesia, postoperative pain, surgery
|How to cite this article:|
Mishra AK, Afzal M, Mookerjee SS, Bandyopadhyay KH, Paul A. Pre-emptive analgesia: Recent trends and evidences. Indian J Pain 2013;27:114-20
| Introduction|| |
Preemptive analgesia is defined as a treatment that is initiated before surgery in order to prevent the establishment of central sensitization evoked by the incisional and inflammatory injuries occurring during surgery and in the early postoperative period.  Owing to this 'protective' effect on the nociceptive system, preemptive analgesia has the potential to be more effective than a similar analgesic treatment initiated after surgery. As a consequence, preemptive analgesia can reduce immediate postoperative pain and also prevent the development of chronic pain by decreasing the altered central sensory processing. 
| Materials and Methods|| |
We have reviewed original research articles, case reports, meta-analyses, randomized control trials (RCTs), as well as reviews based on pain physiology in respect to preemptive analgesia from Medline, Medscape, and PubMed from the year 1993 to 2013. A broad free-text search with restriction to publications in English was undertaken with all variants of terms. "Preemptive analgesia," "postoperative pain," "preoperative," and "preincisional" were entered as major keyword search. Reference lists of retrieved reports and reviews were searched for additional trials. Unpublished reports and abstracts were not considered.
History and Present Status
The idea of pain prevention was first introduced into clinical practice by Crile in 1913 and further developed by Wall and Woolf who suggested that 'simple changes in the timing of treatment can have profound effects on postoperative pain' ,, . The concept of preemptive analgesia to reduce the magnitude and duration of postoperative pain was paved in 1983 by Woolf  who showed evidence for a central component of post injury pain hypersensitivity in experimental studies. Since the original experimental observations suggested that the timing of analgesic treatment in relation to the noxious (surgical) injury was one of the most important issue, studies of clinical preemptive analgesia have been designed to test this hypothesis. Subsequently, an overwhelming amount of experimental data demonstrated that various anti-nociceptive techniques applied before injury were more effective in reducing the post injury central sensitization phenomena as compared with administration after injury. ,
Some reviews have concluded that preemptive analgesia is effective as such,  some have concluded it to be effective only for certain analgesic drugs,  while few others have attributed no beneficial effect to any drug. 
Commonly Used Terms With Respect To Preemptive Analgesia
- Central sensitization - persistent post injury changes in the central nervous system that results in pain hypersensitivity.
- Central hyperexcitability - exaggerated and prolonged responsiveness of neurons to normal afferent input after tissue damage.
- Preincisional treatment for pain - treatment that starts before an initial surgical incision.
- Postincisional treatment for pain - treatment that starts immediately after the end of operation.
The Rationale behind Preemptive Analgesia
Painful or injurious (noxious) stimuli to the body are detected by the free endings of peripheral nerves (primary afferent neurons), jointly called nociceptors. The peripheral terminals of nociceptors act as transducers, converting chemical, mechanical or thermal energy at the site of the stimulus to electrical activity, which is then conducted to the dorsal horn of the central nervous system. [Figure 1]. 
|Figure 1: Tissue damage initiates a number of alterations of the peripheral and the central pain pathways. Central sensitization may outlast the stimuli that triggered the alterations in the fi rst place and thus turn into a 'pain memory' |
Click here to view
Nociceptors are subdivided into different groups depending on their location in various tissues and their response to different stimuli. In general, the myelinated A δ nociceptors are specialized for detecting mechanical and thermal injury and for triggering a rapid sharp pain response, termed 'first pain'. The unmyelinated C nociceptors respond to strong mechanical, thermal and/or chemical stimuli, and they mediate a more delayed burning pain response, termed 'second pain'.
In the dorsal horn, the pain signals are transmitted from the nociceptors to secondary nociceptive neurons. Two classes of dorsal horn neurons, namely the nociceptive-specific neurons (NS neurons) and the wide-dynamic-range neurons (WDR neurons) are involved in the response to and further signaling of pain sensation. NS neurons respond only to pain signals in Aδ and C nociceptors, whereas WDR neurons respond to both non-nociceptive impulses in Aβ fibers (e.g., touch) and nociceptive impulses in Aδ and C nociceptors [Figure 1]. A range of substances are involved in the transmission of nociceptive signals in the dorsal horn, including the excitatory amino acids aspartate and glutamate, and substance P, which acts on N-methyl-D-aspartate (NMDA) and 2-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors.
Depending on the severity of the injury, external stimuli that activate nociceptors and induce pain may or may not result in overt tissue damage. Activation of nociceptors without accompanying tissue damage generally results in a proportionate relationship between the stimulus and the response. Consequently, when the stimulus that caused the pain recedes, the pain disappears without leaving any trace in the nociceptive system.
In contrast, stimuli associated with actual tissue damage initiate a number of alterations, or modulations, of both the peripheral and the central pain pathways. At the periphery, tissue damage results in a local inflammatory response with release of pain-promoting (algogenic) substances from peripheral nerve endings and extraneural sources (e.g., substance P, prostaglandins, serotonin, bradykinin, and histamine). These mediators lead to peripheral sensitization of the nociceptors, resulting in altered transduction and increased conduction of nociceptive impulses towards the CNS. In addition, the barrage of pain signals from the nociceptors onto the NS and WDR neurons in the dorsal horn leads to prolonged alterations in the responsiveness of these neurons. Signals from Aδ and C fibers will be amplified (hyperalgesia), and activity in Aβ fibers will be interpreted not as touch but as pain signals by the WDR neurons (allodynia). This central sensitization may outlast the stimuli that triggered the alterations in the first place and thus become a 'pain memory' [Figure 1].
What are the available methods?
To preemptively cure pain we have a wide variety of armamentarium to suit to the needs of the patient. To overcome acute postoperative pain the following drugs [Figure 2]  and routes are being used recently ⊾
|Figure 2: The pain pathway and interventions that modulate activity at each point|
Click here to view
- Parenteral and oral nonsteroidal anti-inflammatory drugs (NSAIDs)
- Sublingual and intravenous (IV) opioids
- Parenteral NMDA receptor antagonists
- Local anesthetics (LA) for neuraxial administration, peripheral blocks, wound infiltrations, and intraperitoneal instillations.
- Systemic antiepileptics (GABA (gamma-amino butyric acid) analogues).
NSAIDs are a group of drugs which have predominantly analgesic and antipyretic actions. Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), reversibly inhibits both the COX-1 and COX-2 isoenzymes. COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid. Prostaglandins act as messenger molecules in the process of inflammation.
IV NSAIDs are used preemptively in various surgeries, intraoperatively, to prevent pain in the early postoperative period. Simon E et al showed in their study that preoperatively administered intravenous diclofenac effectively reduces post-craniotomy headache even on the 5 th postoperative day; however, the utility of this study was limited due to the lack of randomization.  In a randomized study  conducted in Zagreb, Croatia the authors found that preemptive administration of a combination of low-dose IV ketamine with diclofenac sodium improved postoperative analgesia after laparoscopic cholecystectomy. A randomized, double-blind, controlled trial from China proved that IV flurbiprofen axetil appears to have a preemptive, analgesic effect in patients undergoing radical resection of esophageal carcinoma via the left thoracic approach, and appears to contribute to recovery of respiratory function and reduction of postoperative inflammatory reaction.  Kashefi et al., found in a study that using oral celecoxib 200 mg 2 h before operation is better than using oral acetaminophen 320 mg 2 h before the beginning of surgery for control of postoperative pain in patients who underwent lower extremity orthopedic surgery under general anesthesia. 
Several novel approaches using NSAIDs are evolving recently, for example, NSAID-infiltrated gelatin hydrogel has been used recently in rat model and may serve as a useful analgesic method for the long-term relief of postoperative pain of humans in future. 
Opioids, via their interaction with various opioid receptors produce profound and prolong analgesia, and thus may have a positive role in preemptive analgesia. Campiglia et al.,  demonstrated that in patients undergoing elective abdominal surgery, premedication with sublingual morphine sulfate results in a better control of postoperative pain, compared to premedication with sublingual midazolam and this beneficial effect was apparent in the immediate postoperative period, as well as over the 48-h assessment period.
NMDA Receptor Antagonists
They seem to have a doubtful role in preemptive analgesia as a standalone agent. Some publications proves the lack of its efficacy, as demonstrated by Van Elstraete et al., who showed that small dose of IV ketamine does not seem to be a useful adjunct to remifentanil-based anesthesia during short, painful surgical procedures.  However, there are some very recent evidences published by Gharaei et al., that preemptive low dose IV ketamine (0.1 mg/kg) as a bolus has opioid-sparing effects in opioid abusers undergoing moderate sedation.  A more conclusive evidence of Ketamine as an adjuvant in preemptive analgesia comes from Nesek-Adam V et al  who concluded that the preemptive administration of a combination of low dose IV ketamine with diclofenac sodium improved postoperative analgesia after laparoscopic cholecystectomy; whereas, only IV ketamine at a dose of 0.15 mg/kg did not elicit a preemptive analgesic effect.
Newer novel approaches using ketamine have been seen in recent years. El Sonbaty et al., found that peritonsillar injection of a combination of bupivacaine and ketamine provided efficient postoperative analgesia following adenotonsillectomy in children  and was successful in achieving higher parents' satisfaction as the outcome of surgery. Silva et al., evaluated the effect of ketamine in inhibiting cytokine production and found that epidural injection of 25 mg S (+) ketamine before skin incision reduced the intensity of pain for only 12 h postoperatively and did not alter concentration of cytokines. 
LA are membrane stabilizing drugs which act mainly by inhibiting sodium influx through voltage gated sodium channels, hence inhibiting the generation of action potential. They are used in neuraxial blocks, peripheral nerve blocks, and wound infiltration; often in combination with other drugs mainly opioids. Opioids alone are also frequently administered in the spinal or epidural spaces for analgesia.
Coughlin et al., conducted a systematic review to study the impact of local analgesia timing on postoperative pain in laparoscopic surgery. Twenty-six studies were included in the analysis and it was seen that preemptive administration of LA at the incision site reduces postoperative pain compared with placebo but achieves an analgesic effect similar to that of postincisional anesthetic infiltration. Preemptive LA administered intraperitoneally also decreases postoperative pain compared with both placebo and postoperative infiltration. , The effect of preemptive epidural analgesia on cytokine response and postoperative pain was studied in laparoscopic radical hysterectomy for cervical cancer. It was seen that preemptive epidural analgesia is a reasonable approach for potentially controlling perioperative immune function and even preventing postoperative pain.  In a prospective randomized study, a comparison was made between three preemptive analgesics with local anesthetic -subcutaneous morphine, continuous epidural morphine, and diclofenac sodium. It was concluded that Visual Analogue Scale (VAS) for pain scoring was lowest in the diclofenac group, but time to first request for supplemental analgesia was shortened and more supplemental analgesic was required until 72 h. Epidural morphine did not give the expected effect with comparatively higher rates of minor side effects; whereas, subcutaneous morphine produced some analgesic effects with a lower rate of complication.  In a meta-analysis epidural analgesia was compared to parenteral opioids, and it was found that epidural analgesia regardless of analgesic agent, location of catheter placement, and type of pain assessment, provided better postop analgesia. 
Systemic Antiepileptics (GABA analogues)
GABA analogues such as pregabalin and its developmental precursor gabapentin were originally used as therapeutic adjunct for the management of partial seizures. They have been found to be useful in controlling chronic neuropathic pain as shown in large, double-blind, randomized control studies. , Pregabalin is rapidly absorbed with peak blood concentration reaches in 1 h time. It does not undergo hepatic metabolism and 98% of the absorbed drug is excreted unchanged in urine.
Perioperative pain is thought to involve primary hyperalgesia (peripheral nociceptor sensitization) and secondary hyperalgesia (central sensitization). , Gabapentin and pregabalin appear to have no effect on primary hyperalgesia, but suppress the tissue damage induced hyperexcitability of dorsal horn neurons and hence decrease secondary hyperalgesia. , Analgesic action of gabapentin and pregabalin are mediated through their binding to the alpha-2 delta subunit of voltage gated calcium channels.  The affinity to alpha-2 delta subunit is six times more in pregabalin and so it is six times more potent than gabapentin, but exhibits less side effects than gabapentin. By reducing the hyperexcitability of neurons in the dorsal horn secondary to tissue damage, gabapentin and pregabalin have been useful in the treatment of postoperative pain, anxiolytic effect of these drugs being an added advantage. ,
In a prospective RCT conducted by Dahl et al., gabapentin given as a premedication 1 h before a number of surgical procedures has shown satisfactory anti-nociceptive effect and even reduced the postoperative analgesic requirement. Pregabalin when used as preemptive analgesic, also has significant analgesic effect against postoperative acute bone pain and has some role in controlling visceral and somatic pain. , Single dose gabapentin premedication reduced analgesic requirement 24 h postoperative period significantly in six studies (vaginal hysterectomy, spinal surgery, abdominal hysterectomy, radical mastectomy, and laparoscopic cholecystectomy). ,,,,
In a review of 22 RCTs, it was observed that gabapentin induced decrease in opioid consumption in first 24 h postoperative period was not dependent on gabapentin dose. Therefore, it is not safe to exceed the single highest safe dose of gabapentin (1200 mg) and pregabalin (300 mg) for premedication before surgery. Saraswat V and Arora compared the preemptive analgesic efficacy of gabapentin and pregabalin for postoperative pain after surgeries done under spinal anesthesia.  Sixty patients were randomized to receive either gabapentin 1,200 mg or pregabalin 300 mg 1 h prior to spinal anesthesia and results showed that time to first analgesic requirement was 8.9 h for gabapentin group and 14.7 h for pregabalin group.
Though gabapentin and pregabalin have established their role in effectively reducing the perioperative pain intensity, opioid consumption and opioid related side effects, producing very few adverse effects, further studies are needed to determine the long-term benefits, optimal dose, and duration of treatment of these two drugs.
| Conclusion|| |
There is no evidence as yet to show the superiority of one particular agent and/or technique over another. The various studies indicate that all the modalities discussed above have some potential in reducing postoperative pain either singly or in combination. Moreover, the very term preemptive is being questioned. In a paper titled Preventive Analgesia-Quo Vadimus? Katz et al., have raised doubts about the classic definition of preemptive analgesia. They argue that according to the classic view it is assumed that intraoperative nociceptive stimulus contributes to a greater extent to postoperative pain than postoperative nociceptive stimulus. However, this view is too restrictive and narrow because sensitization is caused by factors other than peripheral nociceptive barrage. A broader and more encompassing approach would be to minimize the deleterious immediate and long-term effects of noxious perioperative afferent input; hence, Preventive Analgesia. The focus of preventive analgesia is not on the relative timing of intervention but on attenuating the impact of the peripheral nociceptive barrage associated with noxious preoperative, intraoperative, and/or postoperative stimuli. 
A better understanding of pain physiology and the increasing diversity of approaches to eliminate pain should benefit patients and help bring to an end the less than satisfactory management of pain in the postoperative setting. Multimodal approaches that address multiple sites along the pain pathway may prove necessary to adequately prevent central sensitization in many surgical procedures. Some of the discussed positive clinical studies in combination with basic science results are probably sufficient to indicate that preemptive analgesia is a valid phenomenon. However, at present we need to find an answer to the question of how to demonstrate the maximal clinical benefits that can be obtained with the use of preemptive treatment. Evaluation of the true importance of preemptive analgesia will have to await further research with new, more comprehensive approaches.
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[Figure 1], [Figure 2]