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Pain is defined as “an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” by the International Association for the Study of Pain (IASP). 1 Pain, as a self-protection mechanism of the body after injury, protects the body from injuries and triggers defensive responses. However, the persistence of pain is not only harmful to body protection but also causes pathophysiological changes such as peripheral hypersensitivity, 2 central hypersensitivity, 3 anxiety and depression. 4 Therefore, pain treatment is important in clinical practice.
According to the three-step analgesic ladder issued by the World Health Organization (WHO), 5 most patients can effectively relieve pain; however, some have a poor response to drugs, such as refractory cancer pain, phantom limb pain, and residual limb pain. Therefore, interventional therapy technology has gradually become an important auxiliary method in pain treatment, which can reduce dependence on opioids as well as adverse drug reactions and improve patients’ quality of life. Therefore, this study reviews interventional therapy technology for pain.
Nerve regulation technology
Radiofrequency thermocoagulation
Radiofrequency thermocoagulation is a method for pain treatment that turns the body into a complete electrical circulation path through working electrodes and dispersed electrodes. It works based on the biological thermal effect of high-frequency AC electromagnetic waves generated by the working electrodes and the differences in temperature tolerance among different nerve fibers. It has been widely used to treat clinical neuropathic pain, such as trigeminal neuralgia (TN) 6 and post-herpetic neuralgia (PHN). 7
A study by Chen Zheng 8 et al. assessed the long-term efficacy and safety of percutaneous radiofrequency thermocoagulation (PRFT) as an alternative therapy for TN. All 38 patients had satisfactory pain relief within 3 days after PRFT, with the median time of pain relief standing at 33 months (range: 4–132 months). No serious intraoperative or postoperative complications were observed, except in six patients who manifested bradycardia. Du Xindan 7 et al. observed the efficacy of CT-guided intervertebral foramen puncture and PRTF treatment for 36 refractory PHN in the T1–T3 spinal innervation area. Their results showed that after PRFT intervention, the measured pain numerical rating scale (NRS) score significantly decreased after 2 months without severe adverse effects.
With an in-depth study of neuroanatomy and advanced temperature control technology, radiofrequency thermocoagulation will become a common minimally invasive technique for the treatment of pain in the future. 7 , 9
Cryoneurolysis
Cryoneurolysis (CNL) is a new analgesic technique that uses low-temperature freezing to reversibly ablate peripheral nerves to temporarily block pain signal transmission and produce long-term analgesic effects, which is particularly beneficial for high-risk patients with persistent pain after surgery. 10 Low-temperature nerve decomposition occurs at −100 °C to −20 °C, and the nerve can undergo Wallerian degeneration; however, the endoneurium, perineurium, and epineurium can remain intact, allowing reversible regeneration of axons from the treatment point to the distal end without lesions and neuroma formation. 16 , 17 The analgesic effect of CNL can last from weeks to months. This technique has been used for the treatment of chronic pain for more than 10 years, mainly for postoperative pain, 10 occipital neuralgia, 11 vertebral facet joint dysfunction, 12 phantom limb pain, 13 chronic neuropathic pain, 14 etc. Sophie et al. 15 evaluated the effectiveness and safety of CNL in the treatment of patients with intercostal neuralgia associated with tumor invasion, and the results showed that the technical and clinical success rates of CNL were 96.7% and 100%, respectively. The mean pain score before treatment was 6.4 ± 1.7, which decreased to 2.4 ± 2.4 on the first day after surgery. The median time to pain relief was 45 days (range 14–70 days). CNL is a safe procedure that can significantly reduce the pain score of patients with intercostal neuralgia associated with tumor invasion. Therefore, compared with other nerve damage methods, CNL has the advantage of causing less damage to adjacent tissue structures, reducing the risk of the neuroma, and ensuring the integrity of regenerative tissue function after pain treatment.
Percutaneous balloon compression
Percutaneous balloon compression (PBC) refers to the process of mechanically pressing the nerves through the expansion of the microballoon with the assistance of an image to relieve pain. In 1983, Mullan and Lichtor 18 first proposed PBC as a treatment method that alleviates TN by selectively destroying large myelinated nerve fibers in the trigeminal nerve. A typical “pear” shape of balloon expansion during surgery is the key to a good effect of PBC. 19 , 20 , 21 Recent studies have shown that patients with apparent “pear-shaped” balloons manifest significantly better treatment efficacy than those without them. 22 In addition to balloon shape, intra-balloon pressure, balloon position, and compression time are also considered to be important factors affecting the surgical effect. 20 , 21
As one of the surgical methods for the treatment of TN, PBC is highly effective and safe and has become an ideal choice for TN patients with poor drug treatment and recurrence of pain after craniotomy or those who are old and frail, intolerable to the surgery, and unwilling to accept craniotomy. The pain relief rate of TN treated with PBC reached 82–97.1%, and the pain relief time was approximately 19–20 months. 23 Studies have shown that some patients experience pain recurrence within 1 month–4 years after PBC. The high-risk factors for recurrence may be related to balloon compression location, nerve recovery after injury, hypertension, diabetes, etc. 21 , 24 , 25 PBC can be repeated in patients with pain recurrence after PBC. The immediate relief rate of postoperative pain after repeated PBC is approximately 93.8%. 25
Chemical ablation
Chemical ablation refers to the use of chemical neurolytics to block pain transmission through Wallerian degeneration of sensory afferent fibers to reduce pain. Chemical neurolytics widely used in clinics include ethanol, phenol and methylene blue, etc. 26 , 29 , 30 Relevant literature studies 26 , 27 , 28 have shown that the neurolytic effect can be evaluated 24–48 h later, but it may be more obvious 3–7 days after surgery, with the duration of the effect ranging from 2 months to 2 years.
Clinically, chemical ablation is often used to treat cancer pain 32 , 33 and knee osteoarthritis. 31 For cancer pain caused by upper abdominal tumors, such as pancreatic cancer, gastric cancer, liver cancer, and esophageal cancer, the three-step analgesic ladder is often ineffective. The neurolytic celiac plexus block (NCPB) is commonly used to reduce pain, improve function, and reduce opioid dependence. Celiac plexus block is a process in which 50%–100% ethanol is injected into specific nerve areas to block pain. 32 Yondonjamts et al. 33 included 56 patients with upper abdominal cancer pain, 28 of whom underwent NCBP, and found that the pain scores, morphine consumption, and morphine-related adverse reactions of patients in the NCBP group were significantly reduced after surgery. It decreased from 78 ± 11.5 mg to 18 ± 9.2 mg within 8 weeks. Some scholars have recently used endovascular denervation to relieve the pain caused by upper abdominal tumors with good results. 34 Therefore, NCPB provides an opportunity for patients with upper abdominal cancer pain to reduce the dose of opioids, thus better relieving pain and improving the overall quality of life.
Spinal cord stimulation
Spinal cord stimulation (SCS) refers to the method of disease treatment by implanting electrodes into the spinal canal and stimulating the spinal cord with a switch pulse current at a specific value. The classic “gate control theory, " proposed by Melzack and Wall in 1965, clarifies the working mechanism of SCS. 35 SCS inhibits the input of noxious stimulation from small unmyelinated nerve fibers (Aδ and C fibers) by stimulating the large myelinated nerve fibers (Aβ fiber) in the column posterior medullae spinalis, thus achieving pain relief. According to various experimental studies, 36 , 37 SCS not only regulates pain-related signal pathways and neurotransmitter balance but also affects inflammation and the generation of pain-related neuropeptides (such as enkephalin and calcitonin gene-related peptide), both of which function to inhibit or alleviate pain. This balance of pain signals may be a major mechanism of SCS in pain relief.
With the advantages of insignificant adverse reactions, little dependence on other methods, and a small wound surface, SCS has become an important measure for the treatment of chronic pain in clinical practice. Clinically, it is often used to treat neuropathic pain and pain caused by chronic ischemic diseases, such as failed back surgery syndrome (FBSS), 38 complexed regional pain syndrome, 39 painful diabetic peripheral neuropathy, 40 and post-herpetic neuralgia, 41 etc. A cohort study by Lisa Goudman et al. 38 investigated the effect of high-dose spinal cord stimulation (HD-SCS) on pain drug use in patients with FBSS. The results showed that during the 4-week SCS trial, patients with neurostimulation-naïve FBSS who underwent HD-SCS had a positive response, with not only a reduction in opioid use but also a 50% reduction in anti-neuropathic pain medications. The patients experienced pain relief by 50% and reduced drug use by 50%. Therefore, SCS can reduce the use of opioids, anti-neuropathic agents, and NSAIDs in patients with chronic pain, thereby reducing adverse drug reactions and opioid epidemics.
Minimally invasive interventional therapy for discogenic pain
Nucleus pulposus ablation
Nucleus pulposus ablation refers to the treatment of herniated intervertebral discs through physical and chemical methods under the guidance of DSA, CT, ultrasound, etc., to reduce the pressure in the intervertebral disc, relieve the compression of nerve roots, and achieve the treatment or relief of pain. At present, NP ablation is performed using low-temperature plasma radiofrequency ablation, 42 targeted disc decompression, 43 laser ablation, 44 and collagenase chemonucleolysis. 45 Nucleus pulposus ablation is widely used clinically because of its advantages such as low trauma, few complications, no damage to spinal stability, and rapid recovery after surgery. According to the statistics of Manchikanti et al., 46 from 2000 to 2013, the proportion of minimally invasive interventional pain therapy for every 100,000 patients with lumbar disc herniation in the United States increased year by year, with an annual growth rate of 7.5% and a total growth rate of 156%.
At present, low-temperature plasma radiofrequency ablation and laser ablation are widely used in clinical practice; however, there is less evidence on which surgical method is more advantageous. Xueqin et al. 42 compared the clinical and radiological characteristics of percutaneous low-power laser discectomy (PLLD) with those of low-temperature plasma radiofrequency ablation for the treatment of neurogenic cervical spondylosis, in which 28 patients underwent PLLD and 30 patients underwent coblation. The results of the cervical MR follow-up at 6 months showed that 17 patients in the PLLD group had significantly improved disc herniation after surgery. This was not observed in the coblation group, and seven of the 17 patients who underwent PLLD showed improvement in disc degeneration. Therefore, PLLD and low-temperature plasma radiofrequency ablation are effective and safe interventional treatments for patients with cervical spondylotic radiculopathy, and better long-term clinical outcomes of PLLD treatment may be related to the improvement of intervertebral disc degeneration.
Percutaneous vertebroplasty
Percutaneous vertebroplasty (PVP) is a minimally invasive interventional technique in which bone cement (usually polymethyl-methacrylate) is injected percutaneously into the vertebra through the pedicle or extrapedicular approach to increase the strength and stability of the vertebra, to prevent collapse, relieve pain, and partially restore the height of the vertebral body. Galibert et al. 52 first reported the use of PVP in patients with aggressive hemangiomas of the cervical spine in 1987. However, PVP could not restore the decreased height of the vertebral body, and percutaneous kyphoplasty (PKP) was clinically performed for >10 years. 53 At present, there are two unified views on pain relief of PVP: (1) cement stabilizes the fractured vertebral body and (2) the physical and chemical effects of cement on neural tissue in the vertebral body. 48
Clinically, PVP and PKP are mainly used for vertebral compression fractures, vertebral metastases, vertebral hemangiomas, and multiple myeloma caused by osteoporosis. 47 , 49 , 50 , 51 A large number of studies shows that 47 , 49 , 50 , 51 acute pain and chronically painful osteoporotic vertebral compression fracture pain remission rates were 90% and 80–100%, respectively, vertebral metastases were 60–85%, and aggressive hemangiomas were 80–100%. Therefore, PVP is a safe and effective method for the treatment of symptomatic vertebral compression fractures, which can prolong patient survival, prevent morbidity, and improve quality of life. 54
Intrathecal drug delivery system
An intrathecal drug delivery system (IDDS) refers to the direct action of intrathecal analgesic drugs on the central nervous system through the circulation of cerebrospinal fluid, thus producing analgesic effects. As a first-line intrathecal drug, morphine is widely used to treat refractory pain caused by malignant or non-malignant diseases. The effectiveness, long-term stability, and superior cost performance of intrathecal analgesia have been clinically confirmed. 55 , 56 , 57 However, Paice et al. 58 showed in a retrospective multicenter study that approximately 15%–20% of patients who received intrathecal analgesia had persistent adverse drug reactions to morphine analgesia or could not effectively relieve pain by increasing the dose of morphine. Therefore, new intrathecal analgesics such as ziconotide and hydromorphone have been used in clinical practice. 55 , 56
Clinically, 80%–90% of the pain symptoms of tumor patients can be relieved by a standard and effective three-step analgesic ladder, 59 however, there are still 10%–20% of patients with pain that is refractory to cancer pain and the effect of conventional drug treatment is not satisfactory or intolerable adverse reactions occur. 60 The IDDS is currently widely used clinically for the treatment of refractory cancer pain. The 2017 Poly Analgesic Conference Consensus proposed that IDDS is no longer considered a remedy after the failure of large doses of systemic opioids and should be considered as one of the preferred treatment options for refractory cancer pain. 59 A follow-up observational study by Gabriel Carvajal et al. 63 evaluated the treatment of refractory pancreatic cancer pain with an IDDS over 11 years. The results showed that long-term IDDS has clear efficacy and safety in the treatment of refractory cancer pain caused by pancreatic cancer. Sayed et al. 61 evaluated the degree of pain relief, efficacy, and safety of IDDS implantation in 160 patients with cancer pain. The results showed that the median pain score before implantation was 7.1, and the median pain decline rate was 2.5 at 1 month after implantation. Pain relief continued 3 months after implantation, and only 3% of patients had the intrathecal pump removed within the first month of infection. Therefore, the use of IDDS can save many patients with severe cancer pain and non-cancer refractory pain and significantly improve their quality of life. Relevant literature has shown that IDDS can prolong the survival of cancer pain patients after effective analgesia. 62
Conclusion
Successful treatment of patients with pain requires approaches involving multiple modes and disciplines, such as physical therapy, psychotherapy, drug therapy, and interventional therapy. This review focuses on minimally invasive interventional therapy for pain ( Fig. 1 ), which provides a reference for clinicians to treat various pain disorders. Such interventions remain invasive, no matter how minimal, so clinicians need to fully grasp the indications and contraindications for each technique. The effectiveness and safety of some interventional techniques need to be further clarified, and more multicenter, large-sample, real-world clinical studies are needed. There is still much room for exploration of minimally invasive interventional treatment technology for pain, which peers in the industry should exploit with concerted effort. Fig. 1 Minimally invasive interventional therapy for pain. Fig. 1
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Declaration of competing interest
We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted.
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Acknowledgements
This study was supported by the Lishui Science and Technology Plan Project (Grant Number: 2022SJZC020) and the Medical Health Science and Technology Project of the Zhejiang Provincial Health Commission (Grant Number: 2020KY1084).