Acute analgesia balancing acts--polypharmacy vs. multimodal management (Proceedings)

Multimodal analgesia, so called “balanced” analgesia, was introduced by Dahl et al in 1990 in order to minimize the adverse effects of opioids. These include respiratory depression, sedation, dysphoria, nausea/vomiting, bradycardia, ileus, constipation, pruritus, urine retention, and opioid induced tolerance or hyperalgesia.  

A second purpose for multimodal analgesia is improved pain control pain in the peri-operative period. This allows for decreased gas anesthetic as well as improved recovery and postoperative comfort. Pain perception is not necessarily a predictable process. The current view of the pain pathway includes transduction, transmission, modulation, projection and perception. Neurophysiologic processes within this pathway are not linear or unidirectional.

Complex cascades of specialized cells, chemical mediators, neurotransmitters, receptors, and ions confer tremendous plasticity such that pain itself is something of a Pandora's box. Use of more than one modality achieves pain control through additive and/or synergistic effects. Recently, a third purpose for multimodal analgesia has been purported, prevention of long-term chronic pain. The incidence of chronic postoperative pain in human beings is high in both soft tissue and orthopedic procedures.  Several studies suggest that human patients experiencing high intensity acute postoperative pain have a higher incidence of chronic pain syndromes. There seems to be no physiologic reason to suspect this would not be the case in veterinary species.

Multimodal analgesia involves administering a combination of opioid and non-opioid analgesic drugs that act at different sites within the peripheral and central nervous systems. In order to minimize adverse effects and achieve optimal outcome, a more modern view may include the use of non-pharmaceutical approaches as well. Examples of such modalities include: rehabilitation, cryotherapy, compression therapy, low-level laser (LLT), acupuncture, transcutaneous electrical neuromuscular stimulation (TENS), ultrasound, and pulsed electromagnetic field therapy (PEMF).

Evidence for the effectiveness of these techniques is growing in the human field; however, there is a paucity of blinded controlled studies in veterinary medicine. There is much anecdotal evidence for their use. For more information on non-pharmaceutical modalities see the manuscript Chronic Pain Control in the Dog: When NSAIDs Don't Work. Use of any technique, pharmaceutical or otherwise, must be accompanied by frequent assessment using subjective and objective measures relentlessly adhering to the ethical tenet “do no harm.”

Principles, rationale and critical analysis of pre-emptive analgesia

In 1983 Woolf et al reported evidence for centrally mediated, post-injury, pain hypersensitivity. This led to the development of pre-emptive analgesia as a means to reduce the magnitude and duration of postoperative pain. The definition of pre-emptive analgesia has gone through permutations and controversy. It was originally defined as an antinociceptive treatment to prevent the establishment of altered central processing of afferent input. By altering central processing the incidence of hyperalgesia and allodynia may be decreased. 

The goals of pre-emptive analgesia are 1) decrease acute pain 2) prevent pain induced modulation of the central nervous system (i.e. the development pathologic pain states in the immediate postoperative period); 3) prevent the development of postoperative chronic pain. When coupled with multimodal techniques, an additional benefit is reduced dosage and therefore adverse effects of any individual modality or pharmaceutical.

Studies in the ensuing decades examined the timing of analgesic treatment with regard to maximal reduction of postoperative pain with mixed results. One comprehensive review (Moinche et al 2006) found a lack of evidence for pre-incisional treatment with NSAIDs, IV opioids, ketamine (but not dextromethorphan), peripheral local anesthetics, and caudal analgesia when compared to post-incisional treatment.5

This review did not dispute the effectiveness of multimodal analgesia in the post-incisional period. Interestingly, this review reported one study comparing the effect of identical pre and post-incisional treatment on long-term pain; the percentage of patients with long-term pain 6 months postoperatively was significantly reduced in the pre-incisional group.  Conversely, a meta analysis by Ong 2005 examining the ability of pre-emptive analgesia to attenuate pain showed an overall beneficial effect most pronounced after epidural, local wound infiltration and systemic NSAID.6

This study concluded that pre-emptive analgesic interventions must be sufficiently dense and long in duration in order to block the transmission of noxious afferent information from the periphery to the cord and brain; central sensitization may not be prevented if the treatment is incomplete or terminated too early. This emphasizes the importance of extending therapy into the post-operative period in order to control inflammatory mediators and nociceptive input.

In evaluating pre-emptive analgesia studies one must consider the following: comparison of pre-incisional vs. post-incisional is different from pre-operative vs. post-operative; the impact of confounders such as ineffective blockade, insufficient duration of treatment, and insufficient dosage on central sensitization; variability in type of surgery, recovery, analgesics, and routes of administration; and relevance of outcomes measurements selected. Important outcomes measurements to consider include: use of rescue analgesic, time to first analgesic, resumption of normal activities, (bowel function, dietary intake, return of mobility), pain scale assessment, physiologic parameters, and behavioral parameters.

Closer analysis of conflicting results has led to a modification of the pre-emptive concept. Current evidence suggests that timing of preventative techniques is less important than prevention of pathologic pain using a combination of techniques that minimize peripheral and central sensitization (i.e. multimodal analgesia). Pre-incisional analgesia appears to offer few clinically significant advantages over preventative multimodal measures administered after (or during) the surgical procedure but prior to return of consciousness (pain perception).

This concept further asserts that extension of multimodal therapy into the postoperative period will likely yield better results when compared to pre-emptive approaches alone with respect to improving pain management.7 The emphasis is on the pathophysiologic process to be prevented: altered sensory processing; therefore, pre-emptive does not necessarily require “before incision.”   The focus is sufficient blockade of afferent signals and not on the timing of such blockade (i.e. preventive rather than pre-emptive). This is a subtle, but central point.

Techniques

It is likely impossible to create a pain-free post-operative experience. However, there is much to offer toward improving the patient's experience of and ability to cope with pain. If ensuring adequate pain relief is to be achieved with minimal adverse effects, it is unlikely to be safely and reliably achieved with opioids alone. Goals: peri-operative analgesic regimen that is highly effective, economically feasible, does not require extended hospitalization (i.e. facilitates rapid discharge) and results in minimal adverse effects and high safety profile. Adequacy of pain control has become an important factor in determining when a human patient can be safely discharged from the hospital.

This should be no less true for veterinary patients. Below is a review of commonly used pharmaceuticals along with appropriate techniques for use in the peri-operative period. Non-pharmaceutical techniques are not traditionally included in the definition of multimodal analgesia. This may be a mistake.

There is a temptation toward “everything but the kitchen sink” analgesia in which our best intentions and perhaps a knee jerk response to our past poor performance in veterinary medicine results in over medicating. The risk here is cumulative adverse effects, prolonged hospitalization, reactionary withdrawal of analgesics due to misinterpretation of perceived adverse effects, excessive and unnecessary medication.  This may be rectified as greater understanding of pain physiology and improved assessment allow us to move from symptom control toward mechanism specific pain management.

Opioids

Opioids remain, at least for the timing being, the corner stone of peri-operative analgesia despite their many drawbacks. With the development of mechanism specific multimodal analgesia, opioids will likely take their place in a supporting and rescue role as safer, more potent non-opioid analgesics become available.  There are many delivery routes available: intramuscular (IM), subcutaneous (SQ), intravenous (IV), intra articular (IA), epidural/intrathecal, transmucosal (feline AND canine). Ultra low dose naloxone, nalbuphine, butorphanol are used to reverse adverse events such as dysphoria while maintaining analgesia.

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Prostaglandins reduce the pain threshold peripherally and so contribute to central sensitization.  NSAIDs inhibit prostaglandin synthesis in the periphery as well as centrally (spinal cord). Data supporting the use of NSAID in the immediate postoperative period is robust in human and animal studies. For example two studies found decreased PGE2, IL-6, IL-8, and TNF alpha in orthopedic wound drainage and CSF in human patients receiving NSAIDs when compared to placebo group. This correlated with decreased post-operative morphine consumption and decreased reported intensity of pain in the NSAID group.

Recent practice guidelines for acute pain management in humans state that all patients should receive around the clock regimen of NSAIDs, COX 2 inhibitors, or acetaminophen unless contraindicated.  Importantly, NSAIDs are associated with hematologic (increased potential for bleeding), renal and gastrointestinal adverse effects.  In light of limited evidence for the increased benefit of NSAIDs delivered pre-incisionally and the risks associated with this class of drugs, it may be prudent to administer in the recovery period.

Local anesthetics

Local anesthetics can be administered by a variety of routes: transdermal patches, local wound infiltration, regional block, epidural and intrathecal, and constant rate intravenous (CRI) infusion. For local wound infiltration (bolus, intra-articular and soaker catheters) regional nerve blockade, and epidural/intrathecal techniques appropriate timing (pre-incision vs. post-incision) is not clear. Given that pre-incisional infiltration is not associated with increased risk it would seem either approach is acceptable. There is good evidence that use of local analgesia is far more important than the precise timing administration.

In the past decade CRI lidocaine has become common in veterinary medicine. Its use in human general anesthesia dates back to 1954. There are clinical trials in humans showing an opioid sparing effect. There are several reports of lidocaine infusion having anesthetic sparing effect in dogs and horses; importantly this does not necessarily correlate with analgesia. Results of canine studies evaluating CRI lidocaine analgesic effect are few and mixed. One study in cats found it not to be effective and due to an increase in sensitivity to adverse effects it is not recommended in felines.

The mechanism by which lidocaine infusion may confer analgesia is unknown; however, because post-operative pain is in large part an inflammatory phenomenon, the inflammatory modulating properties of local anesthetics may be implicated. Additionally, intravenous lidocaine has anti-hyperalgesic and analgesic properties. Current studies in canines report use as a single agent. Further study is needed to evaluate its use as adjunctive therapy.

Lidocaine patches are effective in human analgesia. Few reports are available regarding their use in veterinary species; those that are available report low plasma concentrations. This may not indicate a failure in efficacy since local rather than systemic effect is the intended mechanism. Therefore, a more accurate assessment might be local drug concentration within the target tissue. Ko et al found excellent local absorption (about 4 x plasma concentration) in cats using 5% lidocaine patch. However, no measure of efficacy was reported. This technique warrants further evaluation.

NMDA receptor antagonists

There is increasing evidence that subanesthetic dose ketamine may play an important adjunctive role in post-operative pain management. Single IV dose as well as intra-operative and postoperative CRI has been studied. Decreased use of post-operative morphine, reduced pain scores, and reduced time to achieve improved passive range of joint motion have been reported for human orthopedic patients receiving ketamine. Ketamine has been studied as an adjunctive analgesic in major abdominal surgery with mixed results; however there are dosing differences that complicate interpretation. At least three canine studies support the use of ketamine in the peri-operative period. Recent work does not support its use intrathecally chiefly due to histopathologic evidence for cord damage or as a single agent due to a lack of efficacy in an electrical stimulation nociceptive withdrawal reflex model.

Alpha 2 Agonists

The primary site of action of alpha 2 agonists is thought to be the dorsal horn of the spinal cord. Alpha 2 receptors are found surpassingly and this cannot be ruled out as a site of action. These agents have been administered IM, SQ, IV (bolus and CRI), intrathecally and as an effective additive in regional analgesia in human and veterinary studies. There is evidence to support their use as highly effective analgesics. Importantly, these potent agents are correlated with significant cardiovascular changes including hypertension and physiologic bradycardia even at very low doses administered IV. This must be taken into consideration when selecting patients. Those patients unable to manage increased after load, bradycardia, or reduced visceral blood flow should not receive this class of drug.

Alpha 2 delta legends (gabapentin and pregabalin)

These agents bind to the alpha 2 delta subunit of voltage gated calcium channels (VGCC) located on pre and post synaptic membranes. Although the precise mechanism of action is still being elucidated; decreased numbers of VGCC at the cell membrane resulting in altered neurotransmitter release is expected to play a role. In pathologic pain states the number of alpha 2 delta subunits is upregulated. This finding supports the use of these agents in neuropathic pain. Recently, the use of these agents peri-operatively in human laparoscopic cholecystectomy and hip arthroplasty has been reported.

There is only one canine clinical study using gabapentin in the peri-operative period; no significant effect was reported.  However, the authors cite low dose and lack of sensitivity of pain assessment tools as possible reasons for their results. The dose used (5mg/kg) is well below anecdotal doses used to treat chronic pain in humans and canines.

Table 1: Select analgesic doses

Drug

Canine dose (mg/kg)

Feline dose (mg/kg)

Opioids

Buprenorphine

0.005-0.02 SC,IM,IV, buccal q4-8hr

0.005-0.02 SC,IM, IV, buccal q4-8hr

Fentanyl

0.01-0.04 SC,IM q30-60min

0.005-0.02 SC,IM q30-60min

0.002-0.005 IV q30-60min

0.001-0.003 IV q30-60min

0.005-0.02 mg/kg/hr CRI intra op

0.005-0.01 mg/kg/hr CRI intra op

0.001-0.005 mg/kg/hr CRI post op

0.001-0.003 mg/kg/hr CRI post op

Hydromorphone

0.05-0.2 SC,IM,IV q4-6hr

0.03-0.1 SC,IM q4-6hr

0.05-0.1 IV q4-6hr

0.01-0.05 IV q4-6hr

0.05-0.1mg/kg/hr CRI

0.01-0.05mg/kg/hr CRI

Methadone

0.5-1.0 SC,IM q2-4 hr

0.2-0.5 SC,IM,IV q2-4 hr

 (NMDA antagonist)

0.2-0.5 IV

0.1-0.3 IV

0.025-0.2 mg/kg/hr CRI

0.025-0.1 mg/kg/hr CRI

Morphine

0.25-1.0 SQ,IM q4-6hr

0.05-0.2 SQ,IM q4-6hr

Caution histamine release IV bolus

Caution histamine release IV bolus

0.05-0.1mg/kg/hr CRI

0.025-0.05mg/kg/hr CRI

0.1 preservative free epidural q12-24hr

0.1 preservative free epidural q12-24hr

Naloxone

0.001-0.02 SQ,IM,IV prn opioid reversal

0.001-0.02 SQ,IM,IV prn opioid reversal

NSAIDs

Carprofen

2.2 PO,SC q12hr

1-4 SC single dose (not approved US)

4.4 PO,SC q24hr

Not recommended for oral use

Deracoxib

1-2 q24hr

Firocoxib

5 PO q24hr

Meloxicam

0.1 PO,SC q24hr

0.025-0.05 PO,SC q2-4 days

Tepoxalin

10 PO q24hr

Local Anesthetics

Bupivacaine

1-2 SC, intrapleural

1-2 SC, intrapleural

0.3-0.7 epidural*

0.3-0.7 epidural*

Lidocaine

1-2 SC,IV, epidural

1-2 SC,IV, epidural

0.025-0.05mg/kg/min

Alpha2 Agonists

Atipamezole

0.05-0.1 SC,IM reversal dexmedetomidine

0.05-0.1 SC,IM reversal dexmedetomidine

Dexmedetomidine

0.0005-0.003 IV bolus

0.0005-0.003 IV bolus

0.0005-0.001 mg/kg/hr CRI

0.0005-0.001 mg/kg/hr CRI

NMDA Antagonists

Ketamine

0.010-0.020mg/kg/hr CRI intra op

0.010-0.020mg/kg/hr CRI intra op

0.002-0.005mg/kg/hr CRI post op

0.002-0.005mg/kg/hr CRI post op

Other

Acetaminophen

10-15 PO q8-12hr

Contra-indicated

Gabapentin

5-40 PO q8-12hr

2.5-20 PO q8-12hr

Tramadol

1-5mg/kg q6-8hr

0.25-1mg/kg q6-8h

*Decrease dose by 50% in pregnancy or for intrathecal injection

References available upon request