Pain is a complex physiological and psychological activity, and is one of the commonest clinical symptoms. It is gaining more and more attention as the "5th vital sign" after blood pressure, respiration, pulse, and body temperature. In 2020, the International Association for the Study of Pain (IASP) revised the definition of pain to "an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage".
ISAP classifies pain according to duration as acute pain and chronic pain: acute pain lasts less than 3 months and may be caused by tissue damage (trauma, surgery, etc.) or exacerbation of other chronic conditions (low back pain, breakthrough cancer pain, etc.), while chronic pain is pain that lasts more than 3 months.
According to the Centers for Disease Control and Prevention (CDC), about 20.4% of adults in the United States are experiencing chronic pain in 2019, and about 1.5 billion people worldwide are suffering from pain. With the aging of the population, the prolongation of survival of cancer patients, the increase in the number of surgical units, and the prevalence of chronic diseases, the number of pain patients will further increase, which will be followed by greater demands for clinical analgesic drugs, and higher and higher requirements for analgesic intensity, safety, and medication compliance of analgesic drugs. The development space of the analgesic drug market is enormous.
Till now, analgesic drugs are still dominated by opioids and non-steroidal anti-inflammatory drugs (NSAIDs). However, opioids have a series of adverse effects such as addiction, respiratory depression, nausea, vomiting, and constipation, which have triggered a global opioid crisis, leading to bankruptcy of several opioid companies in the United States due to opioid-related litigations. The prescribing guidelines for opioids for chronic pain, released by CDC in 2016, indicated that non-opioid medications are more suitable for the treatment of chronic pain. From 1999 to 2014, there were more than 165,000 people died from overdoses of opioid pain medications.
Multimodal analgesia is gradually becoming the mainstream prescribing method recommended in therapy guidelines of different countries to achieve the goals of reducing opioid use and side effects of various drugs by using analgesic drugs with synergistic mechanisms. However, existing analgesic drugs still have problems such as unsatisfactory analgesic effects, frequent dosing, and poor patient compliance. There is an urgent need for new non-opioid, long-acting, and potent drugs for pain management to support multimodal analgesia.
Post-surgical pain is the most common acute pain in clinical practice, which usually lasts 3-7 days. In particular, patients experience the most intense pain in the first three days after the surgery. According to the article, about 86% of patients experienced pain after surgery; of these, 75% had moderate/extreme pain during the immediate post-surgical period. According to the China Health Statistical Yearbook, the number of domestic inpatient surgery was 67 million in 2020 (excluding outpatient surgeries, day surgeries, etc.), with a compound annual growth rate (CAGR) of about 7%, and is expected to exceed 100 million in 2026. Standardized perioperative pain management is essential to improve patients' postoperative recovery and quality of life, and to avoid the progression to chronic pain.
Currently, inadequate postoperative analgesia is widespread, and the analgesia rate in China's Grade A tertiary hospitals is only about 30%, while moderate to severe pain remains high (40%~60%). Analgesic drugs and treatment modalities with clinical advantages need to be further promoted and popularized. Modern postoperative pain management guidelines, represented by the concept of enhanced recovery after surgery (ERAS), advocate: "preventive analgesia (e.g. preoperative administration of COX-2 selective inhibitors), multimodal analgesia, individualized analgesia, the focus on inflammation management, and reduction of postoperative opioid use". The American Pain Society (APS) guidelines for postoperative pain management suggest the "only four" analgesic protocols with high-quality evidence and strong recommendations: multimodal analgesia and use of NSAIDs as the cornerstone of postoperative analgesia, local anesthetic analgesia for surgical incisions, and local anesthetic neuraxial analgesia for major thoracic and abdominal surgery.
Epidemiological data suggested that 20% of adults are suffering from pain globally and 10% are newly diagnosed with chronic pain each year. Chronic pain can lead to anxiety and depression, which can seriously affect patient life quality. The problem that chronic pain is not effectively treated has become a health topic of utmost concern to the World Health Organization (WHO). On October 11, 2004, WHO and the International Association for the Study of Pain (IASP) jointly launched the "Global Day Against Pain" (the third Monday of each October), and the following week is the Chinese Week Against Pain. The theme of Day Against Pain is established each year to raise the community's awareness of chronic pain.
PDPN is the most common chronic complication of diabetes mellitus, which is a typical peripheral neuropathic pain (pNP) and belongs to chronic pain. About 16% of diabetic patients suffer from PDPN. In 2013, there were about 22 million patients with PDPN in China, with a diagnosis rate of 77.5% and a treatment rate of 61%. The PDPN CAGR from 2013-2017 was projected to be about 3% based on the prevalence of type II diabetes in China.
Currently, the use of drugs is the main treatment for PDNP. Combinations are often used clinically for pathological features, mainly including pregabalin, duloxetine, opioids, and other antidepressant/anticonvulsant drugs used for super-indications, mostly psychotropic drugs administered orally, with significant CNS adverse effects (e.g., dizziness and nausea, drowsiness, suicidal tendencies, etc.) and a series of problems requiring dose titration, long-term multiple doses, withdrawal reactions, and poor patient response rates. There is an urgent medical need for new, safe, and long-lasting analgesic drugs based on novel mechanisms.
[1] Srinivasa N Raja,et al. The revised International Association for the Study of Pain definition of pain: concepts,challenges,and compromises. Pain. 2020;161(9):1976-1982.
[2] Nicholas M,et al. The IASP classification of chronic pain for ICD-11: Chronic primary pain. Pain. 2019;160(1):28–37.
[3] Treede RD,et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–7.
[4] Treede R, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, et al. Chronic pain as a symptom or a disease: The IASP classification of chronic pain for the international classification of diseases (ICD-11). Pain. 2019;160(1):38–44.
[5] Carla E Zelaya, et al. Chronic Pain and High-impact Chronic Pain Among U.S. Adults, 2019. NCHS Data Brief. 2020;(390):1-8.
[6] Dowell D et al. CDC Guideline for Prescribing Opioids for Chronic Pain-United States.JAMA. 2016;315(15):1624-1645.
[7]Kehlet H, Dahl JB. The value of ''multimodal'' or ''balanced analgesia'' in postoperative pain treatment. Anesth Analg. 1993;77:1048-56.
[8]Wall PD. The prevention of postoperative pain. Pain. 1988;33:289-90.10.
[9] Humble SR, Dalton AJ, Li L. A systematic review of therapeutic interventions to reduce acute and chronic post‑surgical pain after amputation, thoracotomy or mastectomy. Eur J Pian, 2015;19(4):451‑465.
[10]围术期目标导向全程镇痛管理中国专家共识(2021版). 中华疼痛学杂志2021年第17卷第2期.
[11] Gan TJ, Habib AS, Miller TE, et al. Incidence, patient satisfaction, and perceptions of post surgical pain: results from a US national survey[J.Curr Med Res Opin,2014,30(1): 149-160.
[12]《中国卫生健康统计年鉴》. 国家卫生健康委员会编. 2017-2021.
[13]普通外科围术期疼痛管理上海专家共识. 上海医学2021年第44卷第1期.
[14]中国加速康复外科临床实践指南(2021版). 中国实用外科杂志2021年第41卷第9期.
[15] Roger Chou, et al. Management of Postoperative Pain: A Clinical Practice Guideline From the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain. 2016;17(2):131-57.
[16] Daniel S Goldberg, et al. Pain as a global public health priority. BMC Public Health. 2011;11:770.
[17]周围神经病理性疼痛诊疗中国专家共识. 中国疼痛医学杂志. 2020;26(5).
[18]中国2型糖尿病防治指南(2020年版)(上).中华医学会糖尿病学分会.