Multiple non-pharmaceutical methods have been used for patients who have undergone spinal surgery and patients who qualify to receive spinal surgery. One of these non-pharmaceutical approaches is physical therapy. Physical therapy is used to strengthen muscles that can assist in relieving pain from these spinal cord injury (SCI) patients [3]. Physical therapy also aids in preventing muscular atrophy from surgery, which in turn helps stabilize the spine while in recovery and reduce spine pain [4]. Another method that has assisted SCI patients is spinal cord stimulators. Spinal cord stimulators are used to address nerve pain in hopes of preventing surgery or to help with post-surgical pain [5–7]. The neurostimulator mechanism releases specific frequencies that interfere with neuronal signaling of the spinal cord; this has shown improvements in SCI patients and has been proven to help with failed spinal surgery patients [5]. Using non-pharmaceutical methods helps prevent unnecessary pain medication prescriptions, aiming to decrease medication dependency.

Cognitive behavioral therapy (CBT) is a well-applied form of psychotherapy in pain management, which focuses on reducing pain and distress by modifying physical sensations, challenging negative thinking, and helping patients adopt healthier coping mechanisms (Table 1) [8]. CBT applied perioperatively and continued postoperatively has proven to significantly reduce maladaptive coping mechanisms, improve outcomes, and decrease disability in patients with spine surgeries [9, 10].

Transcutaneous electrical nerve stimulation (TENS) is a non-invasive treatment that delivers low-voltage electrical impulses through electrodes placed on the skin to the area impacted by pain (Table 1) [11]. TENS-induced analgesia is postulated to be mediated through peripheral, spinal, and supraspinal mechanisms [12, 13]. TENS has been researched since the 1980s and has been shown to reduce the need for narcotics in postoperative pain relief following spine surgeries [14].

While there will always be a need for some intravenous (IV) or oral pain medication for these neurosurgical patients, non-pharmaceutical approaches possibly decrease the number of drugs these patients need and improve their recovery and quality of life.

Pharmaceutically, many different approaches and combinations of drugs are varied among surgeons and surgery types. A recent study showed that administering morphine alongside other drugs such as ketamine and combination therapy of nonsteroidal anti-inflammatory drugs (NSAIDs) and other non-opiate-like drugs had been shown to maximize pain control while not solely relying on opiates to control pain [15]. There are a lot of new multi-modality pain management regimens that are being studied to remove reliance upon just one drug, specifically opiates. Other examples of non-opiate medications that are used for neurosurgical pain management can be anticonvulsants, tramadol, acetaminophen, lidocaine, scalp blocks, dexmedetomidine, parecoxib, and dexamethasone [16]. All these drugs have been shown to help patients with perioperative pain, and some have been shown to help postoperative pain. Epidural injections and facet injections have been proven to improve spinal cord pain. These modalities can be used for patients who do not want to undergo surgery and have also been shown to help with post-surgical pain that is not alleviating with time [17]. A recent study showed that post-surgical lumbar canal decompression patients showed some relief with bolus epidural fentanyl injection, which improved their pain for a short time [18]. This type of fentanyl injection could help resolve acute short-term pain in patients who undergo spinal surgery, which in turn could decrease the amount of opiates given to these patients [18]. Despite using multiple modalities to help manage pain in neurosurgical patients, it is hard to eliminate opiates due to their ability to help with such acute post-surgical pain [19].

Opiate dependency is one of the leading reasons research aims to find other pharmaceutical pain management medications [20, 21]. A recent study showed, that “26.8 million people were estimated to be living with opioid use disorder (OUD) globally in 2016, with > 100,000 opioid overdose deaths annually, including > 47,000 in the USA in 2017” [22]. Due to the opioid pandemic, the medical community is facing, there is a high demand for further research into how the surgical community can help address postoperative pain without overprescribing potentially addictive medications.

NSAIDs reduce pain and inflammation by inhibiting the production of prostaglandins by blocking cyclooxygenase enzymes [37]. Oral NSAIDs are often used in MMA regimens and are effective agents in postoperative analgesia after lumbar spine surgery [38]. An important consideration with prolonged NSAID use in postoperative spine pain management is that NSAIDs have dose and duration-dependent effects on fusion rates [39].

Acetaminophen is metabolized to p-aminophenol, which crosses the blood-brain barrier and is converted to N-acylphenolamine. N-acylphenolamine blocks cyclooxygenase enzymes and other receptors within the central nervous system inducing analgesia [40]. Acetaminophen enhances MMA in experimental and clinical pain states [41], and perioperative acetaminophen administration can reduce post-surgical pain and narcotic consumption [42].

Gabapentin and pregabalin reduce the excitability of neurons in the brain by decreasing the activation and insertion of calcium channels containing an α2δ subunit, which plays a role in transmitting pain signals [43, 44]. Perioperative administration of gabapentin decreases pain and narcotics consumption [45].

Ketamine is a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. The antagonism of NMDA receptors decreases the release of glutamate, which modulates central sensitization [46]. Ketamine decreases postoperative pain scores and opioid requirements [47] and postoperative analgesia was enhanced by the combination of ketamine and methadone in patients who had spine surgery [48].

Lidocaine’s analgesic effect is multifactorial. Lidocaine primarily exerts its analgesic effect on acute pain by blocking voltage-gated sodium channels and preventing depolarization [49]. IV lidocaine increases the concentration of acetylcholine in the cerebrospinal fluid and enhances the pain inhibitor pathway [50]. It also selectively decreases the conduction of unmyelinated C-fibers by reducing the excitability of the spinal dorsal horn [51, 52]. Intraoperative IV lidocaine infusion has proven effective in diminishing the severity of postoperative pain in patients with spinal fusion surgery [53].

Cebranopadol is an opioid-like agent developed by Tris Pharma, which is not yet FDA-approved but has completed phase 3 trials. Cebranopadol is a mu opioid (MOP) receptor and nociceptin opioid peptide (NOP) receptor agonist (Figure 1) [54]. An abuse potential analysis developed by Tris Pharma suggests that cebranopadol has a lower potential for abuse than tramadol and oxycodone.

Tanezumab is a monoclonal antibody that interferes with pain signals by inhibiting nerve growth factor (NGF) from binding to its receptor (Figure 2) [55]. Tanezumab was in development for the treatment of osteoarthritis pain and was shown to have a potential effect on pain modulation in low-back pain [55] but was rejected by the FDA in March of 2021 due to the high risk for joint destruction and rapidly progressive osteoarthritis at high doses. Despite this medication being rejected by the FDA due to side effects, the pathway used requires further research into its use as an effective option for pain regulation.