Chronic pain is an important and specific healthcare problem, which affects at least 10% of the world’s population.¹ In 1953 Bonica made the first and simplest definition of chronic pain as: ‘pain which persists past the normal time of healing stated’.² He just did not made the definition but also stated its importance: ‘in its late phases, when it becomes intractable, it no longer serves a useful purpose and then becomes, through its mental and physical effects, a destructive force’. In parallel to this explanation, with our current knowledge, we now name chronic pain as a disease or syndrome as it is a multidimensional health problem.^{3 4}

The standard treatment plan of chronic pain is a multidisciplinary approach, which includes pharmacology, physical therapies as well as psychological therapies and surgical interventions.⁵ However, this intensive treatment modality is inadequate for many patients and because chronic pain is sometimes resistant even to opioid drugs, ‘overuse’ or ‘abuse’ of prescription opioids has turned to an ‘opioid crisis’.⁶ This situation leads us to opioid sparing therapies where the inevitable role of neuromodulation starts.

Definition of neuromodulation, in its simplest form, is; the process of inhibition, stimulation, modification or therapeutic alteration of the activities of central, peripheral and also autonomic nervous systems by using electricity.⁶ In fact neuromodulation therapy has been known since 15 AD by an accidental help of a torpedo fish.⁷ But the modern era of neuromodulation starts after the introduction of Melzack and Wall’s gate-control theory.⁸ They stated that there is ‘A gate control system modulates sensory input from the skin before it evokes pain perception and response’. the balance between the activation of small and large neural fibers determines if the gate is open or closed. Stimulation of large touch fibers (like in the situation we rub the painful area) would close the gate and lessen the pain. This description leaded clinicians to perform different modalities of neuromodulation at about the same time in late 60’s. Shealy et al.⁹ reported that the dorsal column stimulator was used to treat pain in the light of this theory and now this technique is called spinal cord stimulation [SCS]. Deep brain stimulation [DBS] was defined for the treatment of cancer pain¹⁰ and followed by the identification of peripheral nerve stimulation [PNS] for chronic pain.¹¹

Deep Brain Stimulation (DBS) Surgically implanted units are used for DBS. Thin electrical leads placed deep in the brain, a small battery is generally placed under collarbone and an extension wire placed under the skin from skull passing down the neck to the battery unit. DBS targets specific sites in the brain with a low electrical mono- or bipolar stimulation: ventral posterolateral nucleus and ventral posteromedial nucleus (VPL/VPM) in the thalamus; periventricular grey matter and periaquaductal grey matter (PVG/PAG) and other regions surrounding the third ventricle and aqueduct of Sylvius, and the rostral anterior cingulate cortex (ACC) posterior to the anterior horns of the lateral ventricles.¹² While the stimulation of VPL/VPM pleasant paraesthesia occurs and overcomes the painful sensation, stimulation of PVG/PAG induces a sense of warmth and analgesia. Stimulation of ACC with high frequency removes the affective aspect of pain.¹²

Spinal Cord Stimulation (SCS) SCS stimulation can be provided either via percutaneously placed epidural electrodes or via surgical paddle leads that implanted with a laminotomy.¹³ Electrodes can be placed between C5 to T11 according to the type and origin of the pain. There are three types of SCS as conventional/tonic SCS, High-frequency SCS and Burst SCS.

In conventional SCS main goal is to mask the sensation of pain with paresthesia or tingling. Stimulations are low frequency (40–100 Hz), high amplitude (3.6–8.5 mA) and pulse widths ranging between 300–600 μs.⁶ Classic SCS treatment is effective for etiologies such as complex regional pain syndrome, failed back surgery syndrome, multiple sclerosis and diabetic neuropathy. This tonic, high charge stimulations are the cause of paresthesia feeling. Although its effect on pain relief, some patients reports that they are also uncomfortable with the sensation of paresthesia. Accordingly, in recent years, two new modalities with different stimulation waveforms and stimulation paradigms have been implemented to the clinical practice.

High-frequency SCS involves a different high frequency (10 kHz) stimulation with amplitude ranging between 1–5 mA and with a pulse width at 30 μs. This frequency is at a sub-threshold level and therefore does not cause paresthesia. Although there are limited data about its efficacy and superiority to conventional SCS, it is shown that high-frequency SCS is a better option for chronic low back pain.⁶

Burst SCS is another novel mode of stimulation where burst frequency is 40 Hz and pulse frequency is 500 Hz. the stimulations are provided in bursts of five pulses (1000 μs). With reduced amplitudes, this modality provides pain relief with either reduced or no paresthesia. Burst SCS has been shown to be superior to SCS in the treatment of lumbosacral component of pain in failed back syndrome but for other indications, there is still limited evidence to reach a conclusion.

Peripheral Nerve Stimulation (PNS) Peripheral nerve stimulation is a less invasive neuromodulation therapy as it does not violate central nervous system, but works with peripheral subcutaneously placed electrode. Electrode is implanted to close proximity to targeted peripheral nerve. This procedure is similar to perineural catheter placement of regional anesthetists. There are two types of PNS; direct PNS or field PNS (PNfS). In PNfS terminal, sensory and cutaneous nerve fibers are targeted for stimulation. Headache, fascial pain, trigeminal neuropathic pain, fibromyalgia, postherpetic neuralgia and complex regional pain syndrome type I-II, coccydynia are some of the indications that PNS/PNfS have been shown to be efficacious.¹⁴

Conclusion Except for all these new treatment modalities and all newly developed technologies, yet we have limited data to compare each method with each other. Probably, over time, some neuromodulation techniques will gain value, while others will loose. There are still unanswered questions related to exact mechanism of action, potential effects of these various stimulation methods on both neuroimmune axis and gene expression, best waveform etc. Clinicians should consider treatment options depending on their clinical conditions, experiences and patient-based basis while relying on the current literature.

Although neuromodulation is currently used just for the treatment of chronic pain; with the development of new technologic devices and by understanding more about the neuronal network it might be used for preventing or treating acute pain in the future by the ‘anesthesiologists not in practice’.

References

1. Jackson T, Stabile V, McQueen K. The Global Burden of Chronic Pain. [Accessed June 21, 2017]. Available from:http://monitor.pubs.asahq.org/article.aspx?articleid=2432061.

2. Bonica JJ. The Management of Pain. Philadelphia, PA: Lea and Febirger; 1953.

3. H. Merskey and N. Bogduk, ‘Classification of chronic pain: descriptions of chronic pain syndromes and definitions of pain terms/prepared by the international association for the study of pain,’ in Task Force on Taxonomy, 2nd edition, 1994, Update 2012, http://www.iasp-pain.org/PublicationsNews/Content.aspx?ItemNumber=1673

4. Treede RD, Rief W, Barke A, 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;160:19–27.

5. Verrills P, Sinclair C, Barnard A. a review of spinal cord stimulation systems for chronic pain. J Pain Res 2016;9:481–492.

6. Deer TR, Jain S, Hunter C, Chakravarthy K. Neurostimulation for Intractable Chronic Pain. Brain Sci, 2019;9:23. doi: 10.3390/brainsci9020023

7. Gildenberg PL. History of Electrical neuromodulation of chronic pain. Pain Medicine. 2006;7:7–13

8. Melzack R, Wall PD. Pain mechanisms: a new theory. Science 1965;150:971–979

9. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain by stimulation of the dorsal columns. Preliminary clinical report. Anesth Analg (Cleve) 1967;46:489–491.

10. Gol, A. Relief of pain by electrical stimulation of the septal area. J. Neurol. Sci. 1967;;5:115–120.

11. Sweet WH, Wepsic JG. Treatment of chronic pain by stimulation of fibers of primary afferent neuron. Trans Am Neurol Assoc 1968;93:103–107.

12. Farrell S, Green A, Aziz T. the Current State of Deep Brain Stimulation for Chronic Pain and Its Context in Other Forms of Neuromodulation. Brain Sci. 2018;8. pii: E158. doi: 10.3390/brainsci8080158.

13. Deer TR, Mekhail N, Provenzano D, et al. the appropriate use of neurostimulation of the spinal cord and peripheral nervous system for the treatment of chronic pain and ischemic diseases: the Neuro- modulation Appropriateness Consensus Committee. Neuromodulation. 2014;17:515–550.

14. Nayak R, Banik RK. Current Innovations in Peripheral Nerve Stimulation. Pain Res Treat. 2018; 2018:9091216 doi:10.1155/2018/909121