Mechanism-Based Treatment and Precision Medicine

Current Treatments

Current pharmacologic therapy involves the use of local anesthetics, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-depressants, anti-convulsants, muscle relaxants, and opioids ( Table 16.1 ), among other drugs. These therapies achieve analgesic effects through a wide range of mechanisms. For example, local anesthetics reversibly block pain impulses by blocking voltage-gated sodium channels. Anti-inflammatory drugs selectively or non-selectively inhibit cyclooxygenases (Cox-1 and Cox-2) to reduce inflammation and sensitization of pain. Most muscle relaxants act centrally. They may activate α2-adrenergic receptor (tizanidine), leading to reduction of excitatory amino acid release from spinal interneurons, or to inhibit 5-HT2 receptor (cyclobenzaprine), leading to diminishing serotonergic descending tone in the spinal cord ventral horn. Anti-convulsants block sodium (e.g. carbamazepine, oxcarbazepine, topiramate, valproic acid) or calcium channels (gabapentinoids, valproic acid). ^, Opioids activate μ, delta, or κ opioid receptors to produce analgesia. Anti-depressants, such as serotonin-norepinephrine reuptake inhibitors (SNRIs, e.g. duloxetine, tramadol, and TCAs), selective serotonin reuptake inhibitors (SSRIs, e.g. Fluoxetine), and selective norepinephrine reuptake inhibitors (NRIs, e.g. tapentadol), activate the descending inhibitory pathways to dampen nociceptive transmission. It is common for one drug to have multiple therapeutic targets or mechanisms. For example, tapentadol acts as a norepinephrine transporter inhibitor and a μ-opioid receptor agonist; Gabapentin primarily works by blocking the a2d1 subunit of voltage-gated Ca ²⁺ channels, but may also modulate other targets such as transient receptor potential channels and N-methyl-D-aspartate (NMDA) receptors. In addition, it may also inhibit γ-amino-butyric acid (GABA) release in the locus coeruleus and stimulate noradrenaline-mediated descending inhibition in the spinal cord.

Monoclonal antibodies are antibodies produced by identical immune cells that are clones of a unique parent cell. Given their high selectivity and long half-lives (weeks), monoclonal antibodies are emerging as the main type of pain therapeutic for multiple targets. Monoclonal antibodies antagonizing the calcitonin gene-related peptide (CGRP) signaling pathway represent a novel and mechanism-specific approach to the prevention and treatment of migraine headaches, as CGRP plays a critical role in neurogenic inflammation and the pathogenesis of migraine. Monoclonal antibodies against CGRP (fremanezumab, galcanezumab, and eptinezumab) or CGRP receptor (erenumab) ^, have shown efficacy in preventing or aborting migraine headaches in high-profile controlled trials without safety issues to date ( Table 16.1 ).

Treatments Under Development

It is noteworthy that Oliceridine is recently FDA-approved for short-term use to treat moderate to severe pain in hospitals or other controlled clinical settings. ( Table 16.2 ). However, pharmacologic inhibitors for these new targets for G protein-coupled receptors, ion channels, and enzymes have achieved limited success. For example, pre-clinical studies have indicated an important role of p38 mitogen-activated protein kinase (MAP) kinase in microglia activation and the pathogenesis of pain. However, most of the p38 inhibitors have failed in clinical trials for different disease conditions either because of poor pharmacokinetic profiles or lack of selectivity. Nerve growth factor (NGF) plays an important role in inflammatory pain and cancer pain, NGF monoclonal antibodies such as Tanezumab, Fulranumab, and Fasinumab are developed for managing chronic pain in humans and in dogs and cats. Anti-NGF treatment alleviated joint pain in patients with osteoarthritis, but also resulted in joint safety events. Further research is needed to determine the clinical importance of these efficacy and adverse event findings. The voltage-gated sodium channel subtype Nav1.7 is one of the best validated targets for human pain. However, the effect of a selective, peripherally restricted Nav1.7 sodium channel blocker PF-05089771 was smaller than that seen with pregabalin.

Interventional Procedures

Interventional procedures employ an array of therapeutic mechanisms. Nerve blocks with local anesthetics, often combined with a corticosteroid, reversibly block nociceptive afferents and reduce irritation/inflammation of the target nerve. Since nerve blocks often only provide short-term therapeutic effects, nerve ablations are sometimes used to provide longer term relief of joint pain (e.g. facet joint, sacroiliac joint, knee, hip, shoulder, and intervertebral disc), neuropathic pain (e.g. trigeminal neuralgia, nerve entrapments), or visceral pain (chronic abdominal or pelvic pain) through radiofrequency denervation, cryoneurolysis, chemoneurolysis, or balloon compression. These procedures provide an irreversible block of nociceptive afferents until nerve regeneration and reinnervation occur.

Surgical Approaches

A wide range of surgical procedures are performed to treat pain by decompressing specific nerves that are compressed or entrapped. Examples include microvascular decompression for trigeminal neuralgia, laminectomy or minimal invasive lumbar decompression for spinal canal stenosis, foraminotomy for foraminal stenosis, and discectomy for intervertebral disc encroachment of the spinal nerve root. These surgeries are performed to mitigate physical compression and/or chemical irritation of the target nerve, improve the blood circulation of the nerves, and relieve pain and other symptoms.

Physical/Cognitive/Behavioral Therapies

The role of physical, cognitive, and behavioral therapies is increasingly recognized in pain management. Although the mechanisms for most of these therapies remain to be elucidated, influential hypotheses or theories have been proposed and frequently cited. Physical therapy, such as exercise, manual therapy, and transcutaneous electrical nerve stimulation, can be used to target specific changes in peripheral tissues and nociceptors, neuropathic pain signs and symptoms, reduced central inhibition and enhanced central excitability, psychosocial factors, and alterations of the movement system. These five categories of pain mechanisms (nociceptive, central, neuropathic, psychosocial, and movement system) are often cited in physical therapies. Cognitive behavior therapy (CBT) is based on the belief that thought distortions and maladaptive behaviors play a role in the development and maintenance of psychological disorders and disability, including chronic pain disorders, and that symptoms and associated distress can be reduced by teaching new information-processing skills and coping mechanisms. Clinical trials and clinical practice support the use and efficacy of these treatments in specific patient populations.