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Multimodal Analgesia: Role of Non Opioid Analgesics

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May L. Chin, MD
Professor of Anesthesiology and Critical Care Medicine
George Washington University Medical Center
Washington, DC


An optimal perioperative experience encompasses effective pain control with minimal side effects from anesthetic and analgesic drugs.  The goals are to facilitate recovery of the surgical patient, enhance patient satisfaction and improve cost effectiveness.  Despite these intentions, national surveys on postoperative pain management in the United States and in Europe report suboptimal pain control as well as significant adverse effects from opioid analgesia.[1-3]

Opioids have traditionally been the cornerstone for pharmacotherapy in the management of postoperative pain.   However we are often faced with situations where monotherapy using opioid alone is inadequate.  A multimodal approach to pain control, or balanced analgesia, is not a new concept.  Treatment strategies which include a combination of analgesic options such as regional techniques and non opioid analgesics have shown improved analgesia, early mobilization and reduced opioid side effects in postoperative patients.[4-6]

Significant strides have been made toward understanding pain mechanisms which lead to sensitization of the nervous system and hyperalgesia.  These mechanisms are more effectively targeted by analgesics other than opioids, such as NMDA antagonists, anticonvulsants, nonsteroidal anti-inflammatory agents, local anesthetics, and alpha 2 agonists.  The use of these agents in a multimodal approach to optimize postoperative pain control will be discussed.

Pathophysiology of Pain

Peripheral and Central Sensitization

It has been recognized for some time that the nervous system is plastic. That is, the nervous system continues to change in the way it responds to ongoing noxious stimulus such as inflammation or injury from surgical trauma. These changes, which occur in the periphery and in the central nervous system, lead to an exaggerated response by the nervous system to normal afferent as well as noxious input, creating a state of heightened sensitivity.

In the periphery, the release of numerous chemical mediators alter the response of high threshold nociceptors, the A delta and C fibers, causing them to fire at a much lower threshold. This results in peripheral sensitization whereby a non painful stimulus produces pain (allodynia) and a painful stimulus results in an exaggerated response (hyperalgesia). Changes in sensory processing also take place in the spinal cord whereby dorsal horn neurons become hyperexcitable when triggered by nociceptive afferent input, resulting in central sensitization. The receptive field properties of these neurons expand such that low threshold A beta mechanoreceptors, which normally do not produce painful sensations, now do so. These changes ultimately result in a state of hypersensitivity manifested as an enhanced response to noxious stimulation.[7]

N-Methyl-D-Aspartate (NMDA) Receptors

The NMDA receptor plays a major role in pain processing in the spinal cord whereby receptor activation results in a hyperexcitable state of the nervous system and increased pain. These receptors are activated by the excitatory neurotransmitter glutamate in the presence of tissue injury. Hence the use of NMDA antagonists may alleviate pain by inhibition of central sensitization.8 The NMDA receptor is a ligand gated ion channel permeable to calcium, potassium and sodium. At resting membrane potential, the NMDA receptor is blocked by a magnesium ion which is removed on depolarization allowing glutamate to activate the receptor.9 The NMDA receptor is composed of several subunits but not all contribute to pain mechanisms. Some subunits in the NMDA receptor are involved with CNS functions, thus blocking this receptor may produce undesirable psychotomimetic effects, memory impairment, ataxia and uncoordinated motor function. Further work related to the use of selective NMDA antagonists for pain control may lead to less CNS side effects.[8]

Repeated C fiber stimulation leads to central sensitization and hyperalgesia. The development of hyperalgesia involves activation of excitatory amino acids result in intracellular events which lead to nitric oxide production. Activation of the mu receptor by opioids interestingly and perhaps ironically also enhances NMDA receptor activation through similar intracellular events, resulting in reduced potency of the opioid.[10] These events are thought to play a role in the development of tolerance to morphine suggesting that neural mechanisms leading to hyperalgesia and tolerance involve NMDA receptor activation.[10-11]

Non Opioid Analgesic Drugs

A. NMDA Receptor Antagonists

Postoperative hyperalgesia is induced by surgical nociception or by anesthetic drugs.[12] An NMDA antagonist administered in the perioperative period as an adjunct analgesic may be opioid sparing and may improve postoperative analgesia by decreasing central sensitization.


Ketamine is an anesthetic agent capable of inducing analgesia, sedation, amnesia and loss of consciousness without cardiorespiratory depression. Even though ketamine has been around for several decades, the association of unpleasant CNS side effects such as hallucinations has discouraged widespread use of this anesthetic agent. With the discovery of the NMDA receptor and further understanding of the role of this receptor in neuronal hyperexcitability, there has been renewed interest in the use of ketamine as an NMDA antagonist in the treatment of pain.

Ketamine is a non competitive antagonist that binds to the phencyclidine binding site of the NMDA receptor. It is available in two forms: racemic ketamine which contains equimolar amounts of S (+) and R (-) and the S (+) stereoisomer which is twice as potent. The S (+) ketamine has four times greater affinity for the NMDA receptor than the R (-) ketamine.9Ketamine has an elimination half-life of 80 to 180 minutes. Its metabolite norketamine is one third as potent and with a longer half–life may contribute to the prolonged analgesic action of ketamine.[9]

There have been several systematic qualitative and quantitative reviews of randomized trials on the use of ketamine in perioperative pain management.[11-17] The reviews collectively reported on large numbers of patients worldwide but several criticisms were noted. In particular, there were large variations in clinical settings, the trials were relatively small, and different ketamine regimens and various routes of administration were utilized. Most of the studies reported reduced pain and analgesic consumption immediately and beyond the duration of action of ketamine when administered in the perioperative period. A small (subanesthetic) dose of ketamine was noted to be safe and afforded opioid sparing but the reviews differed on whether opioid related side effects were decreased.

The optimal timing for perioperative administration of ketamine is not clearly defined. Various dosing regimens have reported effective analgesia with ketamine given in various combinations of dosing such as preincision, intraoperative, at wound closure, and continuing for 48 to 72 hours postoperatively.[18-22] In addition to an opioid sparing effect, it has been suggested that the use of ketamine throughout the perioperative period, concurrent with the duration of noxious stimulus, may prevent or decrease the incidence of persistent postoperative pain. One regimen proposed is as follows: preincisional intravenous bolus of 250-500 mcg/kg followed by either an infusion of 250-500 mcg/kg/hr or intermittent boluses of 125-250 mcg/kg at 30 minute intervals during surgery. In the postoperative period, ketamine may be administered as an infusion at 120 mcg/kg/hr for 24 hours and then at 60 mcg/kg/hr for 48 hours or longer.[11]

Ketamine may be prescribed with opioid analgesics in the postoperative period, administered as intravenous patient controlled analgesia (IVPCA). Although reports on the effectiveness were conflicting,[11][16] a large prospective study of over one thousand patients found the combination of ketamine and morphine in IV PCA to be safe on the general nursing floor.[23] The same study also reported low pain scores and high patient satisfaction. In a randomized double blinded study, the administration of a small dose of ketamine at 250 mcg/kg (in addition to morphine), produced immediate and sustained analgesia in those patients resistant to morphine in the post-anesthesia care unit (PACU). Patients who received ketamine reported better pain scores, a better feeling of well being and wakefulness. They also reported minimal nausea and vomiting or ketamine related side effects.[24]

Despite an abundance of reviews the role of ketamine in perioperative analgesia remains unclear. Further long-term outcome studies are needed, as well as work on the minimum effective dose and the side effect profile of the drug. At the present time, ketamine may be useful in subanesthetic doses as an adjuvant analgesic in opioid tolerant patients, for instance, those with a history of chronic pain or cancer pain. Ketamine may potentially be useful in reducing persistent post surgical pain in patients undergoing surgical procedures associated with higher incidences of persistent surgical pain, such as thoracotomy, mastectomy, and limb amputation procedures.


Dextromethorphan exhibits NMDA receptor antagonist property and a weak affinity for the mu opioid receptor. It has been prescribed as an antitussive agent for many years and has been associated with few side effects. Clinical studies indicated that the administration of preoperative oral dextromethorphan resulted in an attenuated response to tourniquet pain[25] and that preincisional dextromethorphan reduced postoperative morphine requirements.[26] However, a systematic review of the use of dextromethorphan in postoperative pain control did not report consistent analgesic or opioid sparing effects of the drug. The authors were not able to recommend a dosing regimen for the drug nor could they recommend routine clinical use of dextromethorphan for postoperative pain control.[27]

B. Magnesium

Magnesium is more familiar as an anti seizure prophylaxis in preeclampsia and as an antiarrthymic agent than as a drug capable of modulating pain. It is thought that magnesium may have a role in antinocieption by blocking the entry of calcium into the cell at the NMDA receptor thereby preventing the development of central sensitization. The evidence for magnesium as an NMDA antagonist in reducing postoperative pain is limited and weaker than that for ketamine. A systematic review of randomized trials did not provide convincing evidence that magnesium improves postoperative analgesia.[28] However a study looking at the efficacy of intraarticular injections of magnesium and bupivacaine in arthroscopic knee surgery reported the combination to produce better pain control than injections with either drug alone.[29]

C. Anticonvulsant Drugs

We have learned that postoperative pain may be exacerbated by central neuronal sensitization. One of the mechanisms leading to increased pain includes spontaneous discharge from ectopic foci in traumatized nerves. In the postoperative patient, surgical trauma may lead to peripheral and central sensitization resulting in hyperalgesia and allodynia seen as movement evoked pain. Anticonvulsants suppress spontaneous neuronal firing and have been known to be effective in treating chronic neuropathic pain such as postherpetic neuralgia, diabetic neuropathy and cancer related neuropathic pain.[30],[31] Several recent reviews on the use of anticonvulsants in the postoperative period report that anticonvulsants (in particular gabapentin) show promise as adjuvant analgesics by opioid sparing, by their anxiolytic effect, and by contributing to improvement in function.[32-36]

Gabapentin and Pregabalin

Both gabapentin and pregabalin are structural analogs of the inhibitory neurotransmitter gamma-amino butyric acid (GABA), and both bind to alpha 2 delta subunits of voltage dependent calcium ion channels to produce antihyperalgesic effects.[30],[31] A randomized placebo controlled double blinded study in healthy volunteers showed that gabapentin enhanced the analgesic effect of morphine.[37] Others have demonstrated that a single dose of 1200 mg oral gabapentin given preoperatively decreased opioid requirements and improved pain scores both at rest and with movement.[38-10] Perioperative administration of pregabalin has been shown to decrease opioid consumption but was associated with undesirable side effects such as dizziness, blurred vision.[41] Others have found that pregabalin in the dose range of 75 to 300 mg did not reduce postoperative pain or reduce preoperative anxiety and was associated with increased sedation at higher doses.[42] A study comparing gabapentin and ketamine in patients undergoing hysterectomy reported better pain control and less opioid consumption with both analgesic adjuvants. Gabapentin was also associated with significantly less incisional pain six months later.[43] Clearly further studies are needed to identify the anticonvulsant with the best therapeutic profile, the optimal dose and duration of use, the prevention of persistent surgical pain, and the patient population that would benefit most from use of this class of adjuvant analgesic.

D. Non Steroial Anti Inflammatory Drugs

Prostaglandins, produced in the periphery in the presence of inflammation and tissue injury, activate peripheral nociceptors. Spinal neurons may also produce prostaglandins in response to peripheral injury. Cyclooxygenase (COX) inhibitors provide analgesia by inhibiting COX mediated production of inflammatory prostaglandins (COX 2). Centrally, COX inhibition prevents NMDA and AMPA (alpha amino 3 hydroxy 5 methyl isoxazolpropionic acid) receptor activation and the development of central sensitization.[44] Non selective NSAID inhibition of prostaglandins may be associated with serious side effects which include gastric ulceration, renal dysfunction, and bleeding diathesis. Selective COX 2 inhibitors have been associated with fewer gastrointestinal side effects compared to the non selective NSAIDS although there appears to be little difference in analgesic efficacy between the two groups.

NSAIDS are commonly prescribed as adjuvant analgesics in a multimodal approach to pain control. When first introduced, selective COX 2 inhibitors were touted to be more desirable than traditional non selective NSAIDS because of less adverse side effects such as gastropathy. But serious side effects with COX 2 inhibitors soon came to light, in particular cardiovascular and neurological risks related to thrombotic events. These risks, along with a concern for potential risks of surgical bleeding and impaired bone healing, have generated controversy regarding the use of both selective and non selective NSAIDS in the perioperative period.[45]

COX 2 Inhibitors and Cardiovascular Complications

Thromboxane, mediated by COX 1 enzyme in platelets, promotes platelet aggregation after vessel injury. NSAIDS produce reversible inhibition of COX 1. Prostacyclin, produced by endothelium through COX 1 and 2 enzymes inhibits platelet aggregation. Both non selective NSAIDS and COX 2 inhibitors affect the production of thromboxane and prostacyclin, and differentially alter the balance between platelet aggregation and inhibition of platelet aggregation mediated by the endothelium. For instance, rofecoxib, a COX 2 inhibitor (withdrawn in the United States), has been shown to demonstrate little or no effect on platelet inhibition compared to non selective NSAIDS, such as naproxen, ibuprofen, and diclofenac.[46]

Postoperative use of COX 2 inhibitors, valdecoxib, and its parenteral prodrug parecoxib, in coronary artery bypass graft (CABG) patients have been associated with an increased incidence of cardiovascular events, including myocardial infarction, cardiac arrest, stroke, and pulmonary embolism compared to placebo.[47] In a large review of data in persons ranging from 18 to 84 years of age, use of rofecoxib was found to increase the risk of myocardial infarction compared to another COX 2 inhibitor, celecoxib.[48] Rofecoxib studies indicated that cardiac toxicity occurred primarily in older patients (over 65 years) with at least one cardiovascular risk factor. There have not been reports on serious cardiovascular complications with short term use of rofecoxib in the perioperative period.[49] Rofecoxib, valdecoxib and parecoxib are not available in the United States.

A trial investigating COX 2 inhibitor, celecoxib in the prevention of adenomatous polyps was halted because of increased risk for cardiovascular events. In another trial on prevention of Alzheimer’s disease with NSAIDS, the use of celecoxib did not increase cardiovascular risk but naproxen did. This finding was not consistent with other studies and added to the confusion regarding use of NSAIDS.[50]

NSAIDS and Risk of Bleeding

The use of NSAIDS in the perioperative period is often controversial because of concern with increased risk of bleeding from platelet inhibition. Platelets contain the COX 1 enzyme for the production of thromboxane A2 required for platelet aggregation and hemostasis. Theoretically COX 2 inhibitors should not affect platelet function at therapeutic doses.[51] ,[58] The effects of NSAIDS on platelets are reversible and platelet function may return to normal within three days.[58]

A meta-analysis of risk of surgical bleeding in tonsillectomy showed increased risk with postoperative use of NSAIDS.[52] These findings have been challenged by others who cited differences in the dosing of the drug, the duration of treatment, poor surgical technique, and occurrence of bleeding when the drug had been eliminated from the body.[53] Large and small prospective trials as well as other meta analyses report that non selective COX inhibitors and not selective COX 2 inhibitors are associated with increased risk of bleeding[54-57] and that the risk is increased threefold in the presence of anticoagulation.[54] The American Society of Regional Anesthesia and Pain Medicine (ASRA) Third Consensus Conference caution that even though COX 2 inhibitors (celecoxib) do not cause platelet dysfunction, the concomitant use of COX 2 inhibitors and anticoagulants (warfarin) may increase the risk of bleeding by increasing prothrombin time (PT).[58] Aspirin, a commonly prescribed antiplatelet drug, inhibits platelet cyclooxygenase in low doses (60 to 325 mg/day). However higher doses of aspirin (1.5 to 2 gm/day) may inhibit prostacyclin as well, resulting in less inhibition of platelet aggregation and therefore, interestingly, less risk of bleeding compared to low dose aspirin.[58]

NSAIDS and Effect on Bone Healing

Orthopedic and spine surgeons are often reluctant to prescribe NSAIDS in the perioperative period because of concern with impaired bone healing. Animal and clinical studies have indicated that NSAIDS can inhibit bone formation, healing, and fusion.45 This has not been substantiated in humans even though evidence from animal studies suggest impaired bone healing with COX 2 inhibitors.[51] However bone healing is complex and affected by many factors, so one should exercise caution when extrapolating animal data to clinical practice.

Perioperative Cox 2 Inhibitor in Multimodal Therapy

Despite concerns with the use of a COX 2 inhibitor, studies have demonstrated that postoperative use of celecoxib improves analgesia, decreased opioid use and opioid related side effects in the surgical patient, particularly in the early and intermediate postoperative period.[56],[59] The long term benefits Cox 2 inhibitors appear to be less clear.

E. Local Anesthetics

Local anesthetics have been shown to affect coagulation, inflammation, and platelet aggregation.[60] In particular, intravenous lidocaine has been noted to have analgesic, antihyperalgesic and anti-inflammatory properties.[61],[60] Lidocaine, inhibits spontaneous nerve impulses via several mechanisms. These include blockade of sodium channels, inhibition of G protein coupled receptors and inhibition of NMDA receptors.[61] Studies have shown that systemic administration of lidocaine in the perioperative period may be useful in reducing opioid consumption, improving pain control, decreasing ileus and facilitating a shorter hospital stay.[62-66] Although lidocaine infusions appear relatively simple and inexpensive, the analgesic effect has not been consistent[67] nor has the optimal dose for reduction of postoperative pain with minimal side effects been determined.[61]

F. Alpha 2 Agonist

Alpha 2 agonists produce sedation and analgesia with minimal respiratory depression. There are 3 subtypes of alpha 2 adrenoreceptors that mediate the physiologic functions which produce sedation, analgesia, bradycardia and sympatholysis. The locus ceruleus is the predominant site for sedation and the spinal cord the main site for analgesia although peripheral and supraspinal sites are described.

Clonidine and Dexmedetomidine

Clonidine, a less selective alpha 2 agonist compared to dexmedetomidine, has been prescribed for analgesia for a number of years. It can be administered in multiple ways, namely, by oral, parenteral, transdermal, and neuraxial administrations and by intra-articular injection or injection around peripheral nerves.

Dexmedetomidine is a highly selective alpha 2 agonist with a significantly shorter half life than clonidine. The ease of titration with dexmedetomidine has led to the increased use of alpha 2 agonists in the intensive care unit, in surgical locations and in the immediate postoperative period. Dexmedetomidine infusions using small doses (0.2 or 0.6 mcg/kg/hr) has been shown to produce easily reversible sedation and analgesia, associated with stable cardiorespiratory function.[68]

Pharmacodynamic studies conducted in healthy volunteers demonstrated that dexmedetomidine was not associated with clinically significant respiratory depression and that dexmedetomidine was less effective as an analgesic than alfentanil even though a decreased pain response slope was demonstrated.[69],[70] Clinical studies have demonstrated an opioid sparing effect using dexmedetomidine in post surgical patients. Dexmedetomidine administered 30 minutes before the end of surgery at 1 mcg/kg bolus over 10 minutes followed by an infusion at 0.4 mcg/kg /hr resulted in a significant reduction in early postoperative morphine requirements in the PACU.[71] In morbidly obese patients undergoing bariatric surgery, dexmedetomidine infusion at 0.5 to 0.7 mcg/kg/hr instituted one hour prior to the end of surgery and continued in the PACU stay was associated with lower opioid requirements, better pain control, and was not associated with respiratory depression.[72] A recent study reported using intraoperative dexmedetomidine infusion (0.2 to 0.8 mcg/kg/hr) decreased opioid use, antiemetic use and length of PACU stay.[73]


The perioperative experience of a patient is influenced by many factors. A key component to a satisfying and cost-effective surgical experience is optimal perioperative pain control. Traditional analgesics such as opioids are often associated with undesirable side effects. Moreover, opioids may not be effective particularly in the presence of tolerance and hyperalgesia. The increasing array of information on receptors, transmitters, molecular biology and genomics provide opportunities to explore potential “pain targets” utilizing non opioid analgesics. In many instances, incorporating select non opioid analgesics in a multimodal analgesic regimen is associated with better pain control and less opioid side effects.

Although many of these analgesics are used for management of chronic neuropathic pain, the non opioid analgesics discussed serve as useful adjuvant analgesics in optimizing acute pain control. More work needs to be done in determining optimal dosing, timing of drug administration, safety issues, and long term outcome in terms of reduction of chronic or persistent post surgical pain.


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