Commentary

Pain: What We Have Achieved in the Past 25 Years


 

Sait Ashina, MD; Kimberly Sackheim, DO; Christopher Gharibo, MD

Dr. Ashina is Clinical Associate Professor, Department of Neurology, and Director of the Headache Center at NYU Langone Medical Center, New York, NY

Dr. Sackheim is Clinical Assistant Professor, Department of Rehabilitation Medicine, NYU Langone Medical Center, New York, NY

Dr. Gharibo is Associate Professor, Department of Anesthesiology, Perioperative Care, and Pain Medicine, NYU Langone Medical Center, New York, NY

Pain is one of the most prevalent medical complaints and one of the most common reasons people seek medical attention in the United States. Chronic pain has an enormous impact on the individual and is associated with high societal costs. Because of these facts, it is considered a major health problem in the United States. The pathophysiologic mechanisms of acute and chronic pain are not fully understood, and chronic pain remains poorly recognized and undertreated. However, in the past 25 years, there have been major advances in our understanding of pain. New agents, medications, and techniques for the treatment of acute and chronic pain have emerged.

Sait Ashina, MD

Recognizing the undertreatment of pain, the Agency for Health Care Policy and Research at the US Department of Health and Human Services issued the Acute Pain Management: Operative or Medical Procedures and Trauma guidelines in 1992.1 Subsequent years have witnessed increasing use of patient-controlled analgesia, postoperative analgesia, continuous peripheral nerve blocks, and development of new therapeutic and pharmacologic modalities. The recognition of pain medicine as a subspecialty in medicine across multiple specialties is one of the field’s major achievements. The first pain medicine fellowships were accredited in 1993. The number of programs increased to almost 100 by 1999,2 and more programs are being accredited now.

Kimberly Sackheim, DO

With regard to the pathophysiologic mechanisms of chronic pain, we gained a better understanding of central sensitization through research published in the late 1980s that describes activity-dependent synaptic plasticity in the nociceptive pathways.3 Central sensitization is triggered and maintained by nociceptor input. Central sensitization changes the sensitivity of the pain system so that normally innocuous stimulation can activate it. The responses to pain become exaggerated and can be widespread. Substantial progress has been made in understanding the cellular and molecular mechanisms involved in central sensitization, which was initially described as a physiologic phenomenon. Interestingly, glial cells, such as microglia and astrocytes, were reported to contribute to central sensitization in the setting of injury. Advanced neuroimaging techniques reveal that pain is processed in several areas of the brain. PET and functional MRI (fMRI) have provided a deeper understanding of the perception of pain by an extensive mapping of the neural pathways associated with pain: the so-called “pain matrix.”

Christopher Gharibo, MD

In the past 25 years, many new drugs have been introduced for the treatment of acute and chronic pain.4 Antiepileptic and antidepressant medications have been increasingly used for the treatment of several chronic neuropathic pain conditions.

Gabapentin, a structural analog of gamma-aminobutyric acid, was introduced in 1994 as an antiepileptic drug. Placebo-controlled clinical trials have shown gabapentin to be effective in treating pain related to diabetic neuropathy and postherpetic neuralgia.

A successor of gabapentin, pregabalin, is an antagonist of voltage-gated Ca2+ channels. An antiepileptic agent, pregabalin has been shown to be effective in different types of neuropathic pain, including peripheral diabetic neuropathy, post-herpetic neuralgia, fibromyalgia, and cancer chemotherapy-induced neuropathic pain.

Duloxetine, a serotonin and noradrenaline reuptake inhibitor and antidepressant, was shown to be effective in the management of neuropathic pain associated with diabetic peripheral neuropathy, as well as fibromyalgia and chronic musculoskeletal pain, including pain in osteoarthritis and chronic low back pain.

Cyclo-oxygenase-2 (COX-2) inhibitors, developed to avoid the gastrointestinal complications of NSAIDs, were introduced in 1999. Celecoxib was the first COX-2 inhibitor available on the market. COX-2 inhibitors provide anti-inflammatory and analgesic activities similar to those of conventional NSAIDs, but with fewer gastrointestinal complications, which results largely from COX-1 inhibition.

Meloxicam, often classed as a conventional NSAID but with preferential COX-2 inhibition at lower doses, was introduced in the late 1990s and has been extensively used for the treatment of acute and chronic pain.

There is growing interest in the role of cannabinoids in the management of chronic pain. Cannabinoid agents are legal for the treatment of chronic pain in several states, but not legal federally, which discourages most physicians from prescribing them.

In December 1995, the FDA approved oxycontin, an extended-release formulation of oxycodone, a semisynthetic opioid for the treatment of chronic pain. The goal was to deter abuse of the original immediate-release oxycodone by controlling the amount of drug released to avoid the initial “high” associated with the short-acting formulation. Unfortunately, this medication did not deter abuse, and pharmaceutical companies are constantly striving to create new formulations that are more resistant to tampering.

Over the past few years, some formulations of morphine that do deter abuse have been released. Unfortunately, any opioid can still be abused, just not as easily. Opioids have been extensively prescribed for chronic pain conditions, and well-selected patients have benefited from the treatment. However, prescriptions of opioids have increased over the past two decades. As a result, increases in prescription opioid abuse and opioid-related deaths have occurred. State and national efforts have educated clinicians on how to manage pain with opioids and monitor for and treat addiction. Increasing availability of abuse-deterrent opioid formulations and the opioid antagonist naloxone, which is available in pharmacies nationwide, has been of some help.

The role of interventional techniques and use of neuromodulation in pain management has been on the increase in the past two decades. Peripheral nerve stimulation has been used for the treatment of neuropathic pain for 30 to 40 years.5 The introduction of less invasive implantation methods, MRI-compatible stimulators, paresthesia-free stimulation, and dorsal root ganglion stimulation, which are all supported by positive clinical trials, has resulted in a recent increase in the use of neuromodulation for medically refractory patients and those with chronic pain.5 Similarly, spinal cord stimulation has become an alternative for the treatment of chronic pain that is unresponsive to conservative therapies.6 The efficacy of this treatment has improved, and higher-frequency settings are available. Additionally, the use of platelet-rich plasma injections, prolotherapy, and bone marrow injections in pain management have been showing promising results and gaining increasing interest in orthopedics and sports medicine. Unfortunately, there is not enough evidence to support these treatments’ efficacy, and there is no coverage from insurance, which makes them expensive for patients and less attainable.

The American Pain Society has proposed several goals7 with the aim of reducing the burden of chronic pain by improving the understanding of pain pathophysiology and pain treatment mechanisms, developing novel pain therapies, optimizing and testing existing treatment modalities, and promoting education on pain in the future. Much more remains to be learned about the role of peripheral and central sensitization in nociception. Recent advances in imaging techniques may be of great help. With new imaging techniques, including fMRI, it may be possible to measure pain-related brain activity objectively, identify pain biomarkers, and distinguish physical from emotional features of pain. Moreover, advanced imaging may help in the search for new therapeutic agents for acute and chronic pain. More research on potential genetic and environmental risk factors responsible for the development of central sensitization is warranted.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is widely distributed in the nociceptive system in humans. CGRP has been shown to play a role in the pathophysiology of migraine, and blocking it is the rationale behind the recent development of CGRP receptor antagonists and monoclonal antibodies against CGRP for the treatment of migraine. CGRP may play a role in pain transmission and have a proinflammatory role in nociception.8 Improved understanding of these mechanisms may result in the development of new anti-GGRP pharmacologic agents in non-headache pain conditions.

The pharmacogenomics of pain management is an evolving field in pain medicine. More studies are needed to identify genomic variations that can predict response to analgesic drugs. Lastly, further research and studies are needed to suggest use of the stem cell therapy in pain management, but overall, the field is constantly growing, and new therapies are emerging to help avoid the use of potentially addictive medications.

References

1. Acute pain management: operative or medical procedures and trauma, part 2. Agency for Health Care Policy and Research. Clin Pharm. 1992;11(5):391-414.

2. Fishman SM, Ballantyne JC, Rathmell JP, eds. Bonica’s Management of Pain. 4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2009.

3. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288(5472):1765-1769.

4. Kissin I. The development of new analgesics over the past 50 years: a lack of real breakthrough drugs. Anesth Analg. 2010;110(3):780-789.

5. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neurotherapeutics. 2008;5(1):100-106.

6. Bicket MC, Dunn RY, Ahmed SU. High-frequency spinal cord stimulation for chronic pain: pre-clinical overview and systematic review of controlled trials. Pain Med. 2016;17(12):2326-2336.

7. Gereau RW 4th, Sluka KA, Maixner W, et al. A pain research agenda for the 21st century. J Pain. 2014;15(12):1203-1214.

8. Schou WS, Ashina S, Amin FM, et al. Calcitonin gene-related peptide and pain: a systematic review. J Headache Pain. 2017;18(1):34.

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