Advancing Pain Management: A Multifaceted Approach to Reducing Opioid Dependence

Advancing Pain Management: A Multifaceted Approach to Reducing Opioid Dependence

Abstract

Chronic pain represents a significant global health challenge, impacting quality of life, productivity, and healthcare costs. The pervasive use of opioids for pain management has inadvertently fueled a severe opioid crisis, characterized by addiction, overdose, and societal burden. This research report provides a comprehensive overview of the evolving landscape of pain management, emphasizing the urgent need to reduce opioid reliance. We delve into alternative pharmacological and non-pharmacological pain management techniques, explore the neurobiological underpinnings of pain perception and processing, and examine the critical role of interventional pain management strategies. Furthermore, we discuss the burgeoning field of personalized pain therapy, tailoring treatment plans to individual patient characteristics and pain mechanisms. This report aims to provide a nuanced understanding of current best practices and future directions in pain management, ultimately advocating for a holistic, multimodal approach that minimizes opioid use and maximizes patient outcomes.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

1. Introduction

Pain, an unpleasant sensory and emotional experience associated with actual or potential tissue damage, serves as a vital protective mechanism. However, when pain persists beyond the normal healing period (typically defined as 3-6 months), it transitions into chronic pain, a debilitating condition affecting millions worldwide. The International Association for the Study of Pain (IASP) defines chronic pain as pain that persists or recurs for more than three months (Raja et al., 2020). Chronic pain is not merely a symptom; it is increasingly recognized as a complex disease entity with its own biological, psychological, and social dimensions (Gatchel et al., 2007). Its prevalence varies widely across different populations, but estimates suggest that approximately 20% of adults globally experience chronic pain (Goldberg & McGee, 2011). This translates into a substantial economic burden, encompassing direct healthcare costs, lost productivity, and disability payments.

The historical approach to pain management has often relied heavily on opioid analgesics. While opioids can be effective in providing short-term pain relief, particularly in acute settings, their long-term use is associated with significant risks, including addiction, tolerance, hyperalgesia (increased sensitivity to pain), and potentially fatal respiratory depression (Dowell et al., 2016). The overprescription and widespread availability of opioids have contributed significantly to the ongoing opioid crisis, a public health emergency characterized by soaring rates of opioid-related overdose deaths and addiction. This crisis has prompted a critical re-evaluation of pain management strategies and a concerted effort to reduce reliance on opioids.

This research report will explore the evolving landscape of pain management, focusing on alternative approaches that can effectively alleviate pain while minimizing the risks associated with opioids. We will examine both pharmacological and non-pharmacological interventions, delving into their mechanisms of action and clinical efficacy. Furthermore, we will discuss advancements in pain science that are leading to a better understanding of the neurobiological underpinnings of chronic pain and paving the way for more targeted and personalized therapies. The report will also address the role of interventional pain management techniques and the importance of a multidisciplinary approach to chronic pain care.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

2. The Opioid Crisis: A Critical Examination

The opioid crisis is a complex and multifaceted public health emergency with devastating consequences. It is driven by a combination of factors, including the overprescription of opioid pain medications, the availability of illicit opioids (such as heroin and fentanyl), and underlying social and economic determinants of health. A historical turning point was the aggressive marketing of opioids like OxyContin by pharmaceutical companies in the late 1990s, which downplayed the risk of addiction and promoted their use for a wider range of pain conditions (Van Zee, 2009). This led to a significant increase in opioid prescriptions and a corresponding rise in opioid-related addiction and overdose deaths.

The Centers for Disease Control and Prevention (CDC) reports that opioid overdose deaths have increased dramatically in recent decades, with over 80,000 deaths occurring in the United States in 2021 alone (CDC, 2023). The crisis has disproportionately affected certain populations, including rural communities, low-income individuals, and individuals with mental health disorders. Moreover, the rise of illicit fentanyl, a potent synthetic opioid, has further exacerbated the crisis, as fentanyl is often mixed with other drugs, such as heroin and cocaine, without the user’s knowledge, leading to unintentional overdoses.

The consequences of the opioid crisis extend beyond individual health outcomes. It has placed a tremendous strain on healthcare systems, law enforcement agencies, and social services. The economic costs associated with the crisis are also substantial, including healthcare expenses, lost productivity, and criminal justice costs. Addressing the opioid crisis requires a comprehensive and coordinated approach that involves multiple stakeholders, including healthcare providers, policymakers, law enforcement officials, and community organizations.

Strategies to combat the opioid crisis include:

• Reducing opioid prescribing: Implementing guidelines and educational programs for healthcare providers to promote responsible opioid prescribing practices.
• Expanding access to addiction treatment: Increasing the availability of medication-assisted treatment (MAT) for opioid use disorder, which combines medication (such as buprenorphine or naltrexone) with counseling and behavioral therapies.
• Improving access to naloxone: Making naloxone, an opioid overdose reversal medication, widely available to first responders, individuals at risk of overdose, and their families and friends.
• Combating the supply of illicit opioids: Disrupting the trafficking and distribution of illicit opioids through law enforcement efforts and international collaborations.
• Addressing underlying social determinants of health: Addressing factors such as poverty, unemployment, and mental health disorders that contribute to opioid use.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

3. Alternative Pharmacological Pain Management Techniques

While opioids have traditionally been a mainstay of pain management, a growing body of evidence supports the use of alternative pharmacological agents that can provide effective pain relief with a lower risk of adverse effects and addiction. These alternatives can be broadly categorized into several classes:

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): NSAIDs, such as ibuprofen and naproxen, are commonly used to treat mild to moderate pain, particularly pain associated with inflammation. They work by inhibiting cyclooxygenase (COX) enzymes, which are involved in the production of prostaglandins, inflammatory mediators that contribute to pain and fever (Ong et al., 2007). While generally safe for short-term use, long-term NSAID use can increase the risk of gastrointestinal ulcers, cardiovascular events, and kidney damage.

• Acetaminophen: Acetaminophen (paracetamol) is another commonly used analgesic that is effective for mild to moderate pain and fever. Its mechanism of action is not fully understood, but it is believed to involve inhibition of COX enzymes in the brain (Anderson, 2008). Acetaminophen is generally well-tolerated, but it can cause liver damage if taken in excessive doses or by individuals with pre-existing liver conditions.

• Antidepressants: Certain antidepressants, such as tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), have been shown to be effective in treating chronic pain conditions, particularly neuropathic pain (pain caused by nerve damage) (Sindrup & Jensen, 2000). These medications work by modulating the levels of neurotransmitters in the brain that are involved in pain processing, such as serotonin and norepinephrine. Common TCAs include amitriptyline and nortriptyline, while common SNRIs include duloxetine and venlafaxine.

• Anticonvulsants: Anticonvulsants, such as gabapentin and pregabalin, are commonly used to treat neuropathic pain conditions, such as diabetic neuropathy and postherpetic neuralgia (pain after shingles) (Dworkin et al., 2003). These medications work by modulating the activity of voltage-gated calcium channels in the nervous system, which are involved in pain signaling. They are generally well-tolerated, but they can cause side effects such as drowsiness, dizziness, and edema.

• Topical Analgesics: Topical analgesics, such as capsaicin cream and lidocaine patches, can provide localized pain relief by acting directly on pain receptors in the skin. Capsaicin cream works by depleting substance P, a neurotransmitter involved in pain signaling (Mason et al., 2004). Lidocaine patches work by blocking sodium channels in nerve fibers, reducing pain signals. These medications are generally safe and well-tolerated, with minimal systemic side effects.

• Cannabinoids: Cannabinoids, such as cannabidiol (CBD) and tetrahydrocannabinol (THC), have shown promise in treating various pain conditions. CBD is a non-psychoactive cannabinoid that is believed to have analgesic, anti-inflammatory, and neuroprotective properties (Elikottil et al., 2009). THC is the psychoactive component of cannabis and can also provide pain relief, but it can also cause side effects such as anxiety and paranoia. The legal status and availability of cannabinoids vary widely across different jurisdictions.

The choice of pharmacological agent depends on the type and severity of pain, as well as individual patient characteristics and preferences. It is important to note that these medications may not be effective for all patients, and they can also cause side effects. A careful assessment of risks and benefits is essential before initiating treatment.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

4. Non-Pharmacological Pain Management Techniques

Non-pharmacological approaches to pain management offer a valuable complement to pharmacological interventions, and in many cases, can serve as effective alternatives to opioids. These techniques focus on addressing the physical, psychological, and social factors that contribute to chronic pain. They are generally safe, well-tolerated, and empower patients to actively participate in their own care.

• Physical Therapy: Physical therapy plays a crucial role in managing chronic pain by improving physical function, reducing pain, and preventing disability. Physical therapists use a variety of techniques, including exercise, manual therapy, and modalities (such as heat, ice, and ultrasound), to address pain and movement impairments (Sluka et al., 2013). Exercise programs can improve muscle strength, flexibility, and endurance, while manual therapy techniques can reduce joint stiffness and muscle tension. Modalities can help to reduce pain and inflammation.

• Exercise and Activity Modification: Regular exercise and activity modification are essential components of chronic pain management. Exercise can improve physical function, reduce pain, and enhance overall well-being (Geneen et al., 2017). Activity modification involves adapting daily activities to minimize pain and prevent further injury. It is important to start slowly and gradually increase activity levels to avoid exacerbating pain.

• Acupuncture: Acupuncture, a traditional Chinese medicine technique, involves inserting thin needles into specific points on the body to stimulate the flow of energy (Qi) and promote healing. Acupuncture has been shown to be effective in treating various pain conditions, including low back pain, neck pain, and osteoarthritis (Vickers et al., 2012). The mechanisms of action of acupuncture are not fully understood, but it is believed to involve the release of endorphins, natural pain relievers, and modulation of the nervous system.

• Massage Therapy: Massage therapy involves manipulating the soft tissues of the body to relieve pain, reduce muscle tension, and improve circulation. Massage therapy has been shown to be effective in treating various pain conditions, including low back pain, neck pain, and fibromyalgia (Field, 2014). The mechanisms of action of massage therapy are not fully understood, but it is believed to involve the release of endorphins, reduction of muscle spasms, and modulation of the nervous system.

• Cognitive-Behavioral Therapy (CBT): CBT is a type of psychotherapy that helps patients to identify and change negative thoughts, feelings, and behaviors that contribute to chronic pain. CBT has been shown to be effective in treating various pain conditions, including low back pain, fibromyalgia, and headache (Williams et al., 2012). CBT techniques include cognitive restructuring, relaxation training, and activity pacing.

• Mindfulness Meditation: Mindfulness meditation involves focusing attention on the present moment without judgment. Mindfulness meditation has been shown to be effective in reducing pain, anxiety, and depression in individuals with chronic pain (Reiner et al., 2013). Mindfulness meditation techniques include body scan meditation, sitting meditation, and walking meditation.

• Biofeedback: Biofeedback is a technique that allows patients to learn to control physiological responses, such as heart rate, muscle tension, and skin temperature, using electronic monitoring devices. Biofeedback has been shown to be effective in treating various pain conditions, including headache, back pain, and temporomandibular joint (TMJ) disorders (Nestoriuc et al., 2008). Biofeedback techniques include electromyography (EMG) biofeedback, thermal biofeedback, and heart rate variability (HRV) biofeedback.

• Transcutaneous Electrical Nerve Stimulation (TENS): TENS involves applying low-voltage electrical currents to the skin to stimulate nerve fibers and reduce pain. TENS has been shown to be effective in treating various pain conditions, including low back pain, neck pain, and osteoarthritis (Osiri et al., 2012). The mechanisms of action of TENS are not fully understood, but it is believed to involve the release of endorphins and modulation of the nervous system.

The selection of non-pharmacological techniques should be tailored to the individual patient’s needs and preferences. A multidisciplinary approach, combining several different techniques, is often the most effective strategy for managing chronic pain.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

5. Advancements in Pain Science

Significant advancements in pain science have revolutionized our understanding of the neurobiological mechanisms underlying pain perception and processing. These advancements are paving the way for the development of more targeted and effective pain therapies. Key areas of progress include:

• Neuroplasticity and Central Sensitization: Chronic pain is increasingly recognized as a disease of the nervous system, characterized by maladaptive neuroplastic changes in the brain and spinal cord. Central sensitization is a process in which the nervous system becomes hypersensitive to pain, leading to amplified pain signals and pain that persists even after the initial injury has healed (Latremoliere & Woolf, 2009). Understanding the mechanisms underlying central sensitization is crucial for developing therapies that can reverse or prevent this process.

• Role of Glial Cells: Glial cells, such as microglia and astrocytes, were once thought to be passive support cells in the nervous system. However, it is now recognized that glial cells play a critical role in pain processing. Glial cells can become activated in response to injury or inflammation, releasing inflammatory mediators that contribute to pain and central sensitization (Ji et al., 2013). Targeting glial cell activation may be a promising strategy for treating chronic pain.

• Genetic and Epigenetic Factors: Genetic and epigenetic factors play a significant role in pain sensitivity and the development of chronic pain. Certain genes have been identified that are associated with an increased risk of developing chronic pain conditions, such as fibromyalgia and migraine (Diatchenko et al., 2005). Epigenetic modifications, such as DNA methylation and histone acetylation, can alter gene expression and influence pain sensitivity. Understanding the genetic and epigenetic basis of pain may lead to the development of personalized pain therapies.

• Brain Imaging Studies: Brain imaging techniques, such as functional magnetic resonance imaging (fMRI) and positron emission tomography (PET), have provided valuable insights into the brain regions and neural circuits that are involved in pain processing. These studies have shown that chronic pain is associated with changes in brain structure and function, including altered activity in the pain matrix, a network of brain regions that are involved in the perception, modulation, and emotional aspects of pain (Apkarian et al., 2005). Brain imaging can also be used to identify biomarkers that can predict treatment response and guide personalized pain therapy.

• The Endocannabinoid System: The endocannabinoid system (ECS) is a complex network of receptors, enzymes, and endocannabinoids that is involved in regulating various physiological processes, including pain, inflammation, and mood. Endocannabinoids, such as anandamide and 2-arachidonoylglycerol (2-AG), bind to cannabinoid receptors (CB1 and CB2) in the brain and periphery, modulating pain signaling (Lu & Mackie, 2016). Targeting the ECS may be a promising strategy for treating chronic pain, as evidenced by the growing interest in cannabinoids for pain management.

• Immune System Interactions: The immune system plays a crucial role in the development and maintenance of chronic pain. Inflammation, a key component of the immune response, can activate pain pathways and contribute to central sensitization (Sommer, 2012). Moreover, immune cells, such as macrophages and T cells, can release inflammatory mediators that directly activate nociceptors (pain receptors). Targeting immune system interactions may be a promising strategy for treating chronic pain, particularly in inflammatory pain conditions.

These advancements in pain science are transforming our understanding of chronic pain and providing new targets for therapeutic intervention. The development of more effective and targeted pain therapies will ultimately lead to improved patient outcomes and a reduction in opioid reliance.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

6. The Role of Interventional Pain Management

Interventional pain management encompasses a range of minimally invasive procedures aimed at diagnosing and treating pain. These procedures are typically performed by physicians with specialized training in pain management, such as anesthesiologists, physiatrists, and neurologists. Interventional techniques can provide targeted pain relief by blocking pain signals, reducing inflammation, or modulating nerve activity. Common interventional pain management procedures include:

• Epidural Steroid Injections: Epidural steroid injections involve injecting corticosteroids into the epidural space, the space surrounding the spinal cord, to reduce inflammation and pain. Epidural steroid injections are commonly used to treat back pain, neck pain, and radicular pain (pain that radiates down the arm or leg) caused by herniated discs, spinal stenosis, or other spinal conditions (Goodman et al., 2021). While providing temporary relief, concerns exist regarding long term efficacy and potential side effects of repeated injections.

• Nerve Blocks: Nerve blocks involve injecting local anesthetic or other medications around a specific nerve or nerve plexus to block pain signals. Nerve blocks can be used to treat various pain conditions, including neuropathic pain, musculoskeletal pain, and headache. Examples of nerve blocks include median nerve block for carpal tunnel syndrome, occipital nerve block for headache, and facet joint block for back pain (Waldman, 2011).

• Radiofrequency Ablation (RFA): Radiofrequency ablation involves using radiofrequency energy to heat and destroy nerve tissue, thereby disrupting pain signals. RFA is commonly used to treat chronic back pain, neck pain, and arthritis pain. It is often used to target the medial branch nerves that supply the facet joints in the spine (Van Kleef et al., 2010).

• Spinal Cord Stimulation (SCS): Spinal cord stimulation involves implanting a device that delivers low-voltage electrical impulses to the spinal cord to block pain signals. SCS is typically used to treat chronic neuropathic pain conditions, such as failed back surgery syndrome and complex regional pain syndrome (CRPS) (Kumar et al., 2008). Newer SCS technologies, such as burst stimulation and dorsal root ganglion (DRG) stimulation, offer improved pain relief and reduced side effects.

• Peripheral Nerve Stimulation (PNS): Peripheral nerve stimulation involves implanting a device that delivers low-voltage electrical impulses to a peripheral nerve to block pain signals. PNS is used to treat various pain conditions, including neuropathic pain, headache, and facial pain (Deer et al., 2010).

• Intrathecal Drug Delivery Systems (IDDS): Intrathecal drug delivery systems involve implanting a pump that delivers medication directly into the spinal fluid, allowing for targeted pain relief with lower doses of medication. IDDS is typically used to treat severe chronic pain conditions, such as cancer pain and neuropathic pain, that are not adequately controlled with other treatments (Paice et al., 1996).

Interventional pain management procedures should be performed as part of a comprehensive pain management plan that includes pharmacological and non-pharmacological therapies. A careful assessment of risks and benefits is essential before initiating interventional procedures. In particular, procedures such as epidural steroid injections should be used judiciously due to concerns surrounding long-term efficacy and potential side effects. The evidence for some interventions, particularly for chronic low back pain, can be weak, and patient selection is crucial (Chou et al., 2009).

Many thanks to our sponsor Esdebe who helped us prepare this research report.

7. Strategies for Personalized Pain Therapy

Personalized pain therapy, also known as precision pain medicine, represents a paradigm shift in pain management, moving away from a one-size-fits-all approach to tailoring treatment plans to individual patient characteristics and pain mechanisms. This approach recognizes that pain is a complex and heterogeneous experience, with different individuals responding differently to the same treatments. Strategies for personalized pain therapy include:

• Phenotyping and Endotyping: Phenotyping involves identifying distinct subgroups of patients with chronic pain based on clinical characteristics, such as pain location, intensity, duration, and associated symptoms. Endotyping involves identifying the underlying biological mechanisms that drive pain in different subgroups of patients. Combining phenotyping and endotyping can help to identify patients who are most likely to benefit from specific treatments (Davis, 2017).

• Biomarkers: Biomarkers are measurable indicators of a biological state or condition. Biomarkers can be used to diagnose pain conditions, predict treatment response, and monitor disease progression. Potential biomarkers for chronic pain include genetic markers, inflammatory markers, brain imaging markers, and neurophysiological markers (Hashmi et al., 2013).

• Quantitative Sensory Testing (QST): Quantitative sensory testing involves measuring the sensitivity of the nervous system to different stimuli, such as pressure, heat, and cold. QST can be used to identify sensory abnormalities that are associated with chronic pain, such as allodynia (pain from a normally non-painful stimulus) and hyperalgesia (increased sensitivity to pain). QST can also be used to predict treatment response and monitor treatment effectiveness (Rolke et al., 2006).

• Psychological Assessment: Psychological factors, such as anxiety, depression, and catastrophizing, can significantly influence pain perception and coping. Psychological assessment can help to identify patients who may benefit from psychological interventions, such as CBT and mindfulness meditation.

• Pharmacogenomics: Pharmacogenomics involves studying the role of genes in drug response. Genetic variations can influence how individuals metabolize and respond to pain medications. Pharmacogenomic testing can help to identify patients who are more likely to experience side effects from certain medications or who are less likely to respond to treatment (Lee et al., 2005).

• Machine Learning and Artificial Intelligence: Machine learning and artificial intelligence (AI) are emerging as powerful tools for personalized pain therapy. Machine learning algorithms can analyze large datasets of clinical and biological data to identify patterns and predict treatment outcomes. AI can also be used to develop personalized treatment plans and provide real-time feedback to patients and clinicians (Waljee et al., 2017).

Implementing personalized pain therapy requires a multidisciplinary approach that involves close collaboration between physicians, psychologists, physical therapists, and other healthcare professionals. It also requires access to advanced diagnostic technologies and data analysis tools. While personalized pain therapy is still in its early stages of development, it holds great promise for improving pain management and reducing opioid reliance. The move towards a more individualized, targeted approach to treatment based on underlying pain mechanisms represents a significant advance in the field.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

8. Conclusion

The management of chronic pain is a complex and evolving field. The opioid crisis has highlighted the urgent need for alternative pain management strategies that minimize the risks associated with opioid use. A multimodal approach, combining pharmacological, non-pharmacological, and interventional techniques, is essential for providing effective and individualized pain relief. Advancements in pain science are leading to a better understanding of the neurobiological mechanisms underlying chronic pain, paving the way for more targeted and personalized therapies. Personalized pain therapy, based on phenotyping, endotyping, biomarkers, and pharmacogenomics, holds great promise for improving pain management and reducing opioid reliance. Future research should focus on developing and validating personalized pain therapy strategies, improving access to non-opioid pain management options, and addressing the social and economic factors that contribute to chronic pain. The ultimate goal is to provide comprehensive and compassionate pain care that improves the quality of life for individuals living with chronic pain.

Many thanks to our sponsor Esdebe who helped us prepare this research report.

References

• Anderson, B. J. (2008). Paracetamol (acetaminophen): mechanisms of action. Paediatric Anaesthesia, 18(10), 915-921.
• Apkarian, A. V., Bushnell, M. C., Treede, R. D., Zubieta, J. K., & Borsook, D. (2005). Human brain mechanisms of pain perception and regulation in health and disease. European Journal of Pain, 9(4), 463-484.
• Centers for Disease Control and Prevention (CDC). (2023). Overdose Deaths Involving Opioids, 2021. https://www.cdc.gov/nchs/products/databriefs/db457.htm
• Chou, R., Huffman, L. H., American Pain Society, & American College of Physicians. (2009). Nonpharmacologic therapies for acute and chronic low back pain: a review of the evidence for an American Pain Society/American College of Physicians clinical practice guideline. Annals of Internal Medicine, 151(3), 181-194.
• Davis, K. D. (2017). What is the phenotype of chronic pain?. The Journal of Pain, 18(1), 1-5.
• Deer, T. R., Pope, J. E., Hayek, S. M., Narouze, S., Provenzano, D. A., & Benyamin, R. M. (2010). The Polyanalgesic Consensus Conference (PACC): recommendations for improving the quality of pain management. Neuromodulation: Technology at the Neural Interface, 13(2), 77-98.
• Diatchenko, L., Slade, G. D., Nackley, A. G., Bhalang, K., Sigurdsson, A., Belfer, I., … & Maixner, W. (2005). Genetic basis for individual variations in pain sensitivity and tolerance. The Journal of Pain, 6(3), 141-145.
• Dowell, D., Haegerich, T. M., & Chou, R. (2016). CDC guideline for prescribing opioids for chronic pain—United States, 2016. MMWR. Recommendations and Reports, 65(1), 1-49.
• Dworkin, R. H., Backonja, M., Rowbotham, M. C., Allen, R. R., Argoff, C. R., Bennett, G. J., … & Farrar, J. T. (2003). Advances in neuropathic pain: diagnosis, mechanisms, and treatment recommendations. Archives of Neurology, 60(11), 1524-1534.
• Elikottil, J., Gupta, P., & Gupta, K. (2009). The potential role of medical cannabis in the treatment of arthritis. Mayo Clinic Proceedings, 84(8), 713-725.
• Field, T. (2014). Massage therapy research review. Complementary Therapies in Clinical Practice, 20(4), 225-232.
• Gatchel, R. J., Peng, Y. B., Peters, M. L., Fuchs, P. N., & Turk, D. C. (2007). The biopsychosocial approach to chronic pain: scientific advances and future directions. Psychological Bulletin, 133(4), 581.
• Geneen, L. J., Moore, R. A., Clarke, C., Martin, D., Colvin, L. A., Smith, B. H., & Torrance, N. (2017). Physical activity and exercise for chronic pain in adults: an overview of Cochrane Reviews. *Cochrane Database of Systematic Reviews, (4).
• Goldberg, D. S., & McGee, S. J. (2011). Pain as a global public health problem. BMC Public Health, 11(1), 770.
• Goodman, B. S., Posey, J. W., & Heapy, A. M. (2021). Epidural steroid injections for lumbar spinal stenosis and disc herniation: a systematic review and meta-analysis. Pain Medicine, 22(9), 2001-2013.
• Hashmi, J. A., Baliki, M. N., Huang, L., Baria, A., Hermann, N., Schnitzer, T. J., & Apkarian, A. V. (2013). Shape shifting pain: chronification of back pain shifts from nociceptive to emotional circuits. Brain, 136(9), 2751-2768.
• Ji, R. R., Chamessian, A., & Zhang, Y. Q. (2013). Pain regulation by glial cells: mechanisms and implications for persistent pain. Nature Reviews Neuroscience, 14(6), 365-380.
• Kumar, K., Hunter, C., Demeria, D., et al. (2008). Spinal cord stimulation for chronic pain: systematic review and meta-analysis. Neurosurgery, 63(4), 762-776.
• Latremoliere, A., & Woolf, C. J. (2009). Central sensitization: a generator of pain hypersensitivity by central neural plasticity. The Journal of Pain, 10(9), 895-926.
• Lee, C. R., Goldstein, J. A., & Michelson, D. (2005). Pharmacogenomics of pain management. Pain Medicine, 6(S1), S3-S13.
• Lu, H. C., & Mackie, K. (2016). An introduction to the endogenous cannabinoid system. Biological Psychiatry, 79(7), 516-525.
• Mason, L., Moore, R. A., Derry, S., Edwards, J. E., & McQuay, H. J. (2004). Systematic review of topical capsaicin for the treatment of chronic pain. BMJ, 328(7446), 991.
• Nestoriuc, Y., Martin, A., Rief, W., & Andrasik, F. (2008). Biofeedback treatment for headache disorders: a meta-analysis. Journal of Consulting and Clinical Psychology, 76(2), 130.
• Ong, C. K., Lirk, P., Tan, C. H., & Seymour, R. A. (2007). An evidence-based update on nonsteroidal anti-inflammatory drugs. Clinical Medicine & Research, 5(1), 19-34.
• Osiri, M., Welch, V., Brosseau, L., Shea, B., Tugwell, P., Wells, G. A., & McGowan, J. (2000). Transcutaneous electrical nerve stimulation for knee osteoarthritis. *Cochrane Database of Systematic Reviews, (4).
• Paice, J. A., Penn, R. D., & Shott, S. (1996). Intraspinal morphine for chronic pain: a retrospective, multicenter study. The Journal of Pain and Symptom Management, 11(2), 71-80.
• Raja, S. N., Carr, D. B., Cohen, M., Finnerup, N. B., Flor, H., Gibson, S., … & Scholz, J. (2020). The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain, 161(9), 1976-1982.
• Reiner, K., Tibi, L., & Lipsitz, J. D. (2013). Mindfulness-based interventions for chronic pain: a systematic review. Pain Medicine, 14(1), 56-73.
• Rolke, R., Baron, R., Maier, C., Tölle, T. R., Treede, R. D., Beyer, A., … & Birklein, F. (2006). Quantitative sensory testing (QST) in the assessment of neuropathic pain. European Journal of Pain, 10(8), 701-718.
• Sindrup, S. H., & Jensen, T. S. (2000). Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain, 83(3), 389-400.
• Sluka, K. A., Skyba, D. A., Radhakrishnan, R., & Clauw, D. J. (2013). Neuronal mechanisms underlying musculoskeletal pain and fatigue. *Pain, 154 Suppl 1, S164-S171.
• Sommer, C. (2012). Role of the immune system in chronic pain. Pain, 153(3), 461-464.
• Van Kleef, M., Vanelderen, P., Cohen, S. P., Diependaele, S. P., King, J. S., & Kapural, L. (2010). Radiofrequency denervation for chronic low back pain. Pain Medicine, 11(6), 963-972.
• Van Zee, A. (2009). The promotion and marketing of oxycontin: commercial triumph, public health tragedy. American Journal of Public Health, 99(2), 221-227.
• Vickers, A. J., Cronin, A. M., Maschino, A. C., Lewith, G., MacPherson, H., Foster, N. E., … & Linde, K. (2012). Acupuncture for chronic pain: individual patient data meta-analysis. Archives of Internal Medicine, 172(19), 1444-1453.
• Waldman, S. D. (2011). Pain management. Elsevier Health Sciences.
• Waljee, J. F., Higgins, P. D., & Gruber, J. (2017). Machine learning in inflammatory bowel disease: opportunities, challenges, and future directions. Inflammatory Bowel Diseases, 23(5), 721-729.
• Williams, A. C. D. C., Eccleston, C., & Morley, S. (2012). Psychological therapies for the management of chronic pain (excluding headache) in adults. *Cochrane Database of Systematic Reviews, (11).