Multimodal Pain Management Approaches in Neurosurgery

Meeting highlights from Spine Summit: 33rd Annual Meeting of the Section on Disorders of the Spine and Peripheral Nerves

Neuromodulators and preemptive analgesia were presented by Sharad Rajpal, MD, during Spine Summit, the 33rd Annual Meeting of the Section on Disorders of the Spine and Peripheral Nerves. Dr. Rajpal is a neurosurgeon specializing in minimally invasive and complex spine and brain tumor surgery at Boulder Neurosurgical & Spine Associates in Colorado.

“When patients come to our office complaining of pain,” Dr. Rajpal said, “they are seeking a solution to help with pain management and get their lives back on track. A surgical procedure, no matter how small or large, always entails an element of worsening of pain. It is critical, especially given the worsening opioid crisis in the US, that patients maintain a controlled level of pain throughout their treatment, including perioperatively. Several studies have shown that multimodal approaches to pain control are favorable to narcotics alone, owing to both reduced addiction potential and lower doses of needed opioids.”

Dr. Rajpal continued, “I have always been interested in multimodal approaches to pain control. I spent several years researching and studying ways to prevent hyperalgesia in animal models, in hopes of one day translating this work into clinical practice.”
3d rendering of nerve cells, concept for neurologic diseases.It is critical, especially given the worsening opioid crisis in the US, that patients maintain a controlled level of pain throughout their treatment, including perioperatively. Photo

Modulation of Pain Signals

  • For Peripheral Sensitization: In 2007, Rocha et al detailed the release of several algogenic substances through the cellular membrane after tissue injury, including bradykinin, acetylcholine, histamine, tumor necrosis factor α, serotonin, prostaglandin, potassium, substance P, and glutamate.

Damage to tissue activates nociceptors, which leads to the release of inflammatory mediators. The release of these mediators, combined with increased nociceptor excitability, lead to hyperalgesia.

  • Leading to Central Sensitization: Substance P and glutamate activate the dorsal brain N-methyl-D-aspartate (NMDA) receptor. This activation, combined with persistent C-fiber activation, leads to hyperalgesia and allodynia.

Perioperative Pain Management

  • Traditional perioperative pain management consists of opioid medications, which target central mechanisms involved in pain perception.
  • In multimodal analgesia, several agents act at different sites along the pain pathway. Multimodal analgesia reduces dependence on a single medication and mechanism. The overall opioid dose and opioid-related side effects are reduced.
  • Preventative analgesia employs multimodal pain control techniques and reduces sensitization by preoperative, intraoperative, and postoperative stimuli via treatments administered at any time in the perioperative period.

Preemptive Analgesia—Challenges and Implementation Strategies

Preemptive analgesia is defined as treatment that starts before surgery and prevents the establishment of central sensitization caused by incisional and inflammatory injury.1 It is antinociceptive treatment that prevents the establishment of altered processing of afferent input, which would otherwise amplify post-operative pain. It is administered before surgery—before the onset of noxious stimuli, and it may reduce the needed amount of anesthesia and postoperative analgesia.

Challenges: Patients with chronic pain are already sensitized. So it may be harder to achieve successful preemptive analgesia in such patients.2 A 2002 comparison of pre- vs postincision antinociceptive interventions yielded contradictory results,3 and inflammatory injury is a concern as well.1 A 2014 paper asserted that the duration and efficacy of preemptive analgesia are more important than preoperative timing.4

Strategies for Implementing: Preemptive analgesia includes local anesthesia, nerve block, epidural block, subarachnoid block, IV analgesics, and ant-inflammatory drugs.5 Strategies are employed along the ascending input path to the brain or on descending modulation from the brain.5 At the site of trauma, local anesthetics and anti-inflammatory drugs are given, local anesthetics at the level of the peripheral nerve. At the level of the dorsal horn, local anesthetics, opioids, and α2 agonists are given. At the level of the brain, opioids and α2 agonists are given.

The 2016 Guidelines on the Management of Postoperative Pain

This clinical practice guideline recommends nonsteroidal anti-inflammatory drugs (NSAIDs), gabapentin or pregabalin, and ketamine. The guideline was issued with input from the American Pain Society, American Society of Regional Anesthesia and Pain Medicine, and American Society of Anesthesiologists. The guidelines detail recommendations for the use of NSAIDs, antiepileptics, and ketamine.6

Acetaminophen and NSAIDs are recommended in patients without contraindications. They inhibit prostaglandin synthesis by inhibiting cyclooxygenase-1 (COX-1).

Celecoxib is a COX-2 inhibitor and celecoxib is minimally active at baseline. It reduces pain by preventing inflammation, causing hyperalgesia and allodynia. Celecoxib 200-400 mg PO 30-60 minutes pre-operatively maintains platelet function, gastrointestinal mucosal integrity, and renal function.

Gabapentin binds to the α2 subunit of voltage-dependent Ca++ channels. Though a role is implied in the name of the compound, it exerts no γ-aminobutyric acid (GABA) activity. Gabapentin prevents the development of central excitability by stabilizing the neuronal membrane and decreasing the subcutaneous response to pain fiber signals. It is antihyperalgesic. In combination with NSAIDs, gabapentin causes a synergistic reduction in hyperalgesia associated with peripheral inflammation. Side effects are somnolence, dizziness, confusion, and ataxia. Since gabapentin is not metabolized, no significant toxicity occurs.

The primary mechanism of ketamine is N-methyl-D-aspartate (NMDA) receptor antagonism. Ketamine exerts preventative analgesic effects by modulating central sensitization and decreasing acute and chronic post-operative pain. Stimulation of the NMDA receptor is involved in the development and maintenance of persistent postoperative pain, hypersensitivity, windup, allodynia, opioid-induced tolerance, and opioid-induced hyperalgesia.


Much confusion and controversy surround the terms preemptive vs preventative analgesia. Analgesic strategies used in more extensive surgeries require interventions capable of preventing central sensitization throughout the perioperative period. Multimodal approaches that address multiple sites along the pain pathway may prove necessary to prevent central sensitization adequately.

Dr. Rajpal said, “This topic is relevant to all physicians who treat patients with pain, not just surgeons. And pain control is scrutinized more closely by society and the government. We need more clinical studies to better understand and interrupt pain pathways in our efforts to help our patients in acute and chronic pain.”

Updated on: 05/11/19
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