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Chronic Pain and Neuromodulation

Chronic Pain and Neuromodulation

Neuromodulation is a safe, effective, painless, and ultrasound guided invasive technique that consists in the application of low frequency electric currents (or chemical substances) to the peripheral nervous system or central nervous system, which serves to increase or decrease the excitability of a group of neurons. Currently, neuromodulation is used as a therapy against a diverse group of disorders, such as epilepsy, chronic pain, Parkinson’s, neurogenic bladder, spinal injury, and even depression.  1 Electrical neurostimulation systems, along with implant systems of medication delivery, are included in the field of neuromodulation.

Broadly speaking, chronic pain can be classified as nociceptive (visceral and somatic), neuropathic (central nervous pain and peripheral pain), and mixed. However, the World Health Organization partnered with the International Association for the Study of Pain (IASP) to form the ‘IASP Task Force’ with the intent of creating a more precise classification that infers etiology, location, and mechanism of pain.2 As of June, 2018, the resulting classification currently accepted by WHO is as follows3 :

  • Chronic Primary Pain
  • Chronic Cancer Related Pain
  • Chronic Post-Surgical or Post-Traumatic Pain
  • Chronic Secondary Musculoskeletal Pain
  • Chronic Secondary Visceral Pain
  • Chronic Neuropathic Pain
  • Chronic Secondary Headache or Orofacial Pain

In 2016, research was conducted by the National Center for Health Statistics to establish the prevalence of chronic pain and high-impact chronic pain. They concluded that “an estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain (that which frequently limits an active life, including work), with higher prevalence of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.” 4

Figure 1 - Shows the prevalence of chronic pain in the United States in 2016
Figure 1 – Shows the prevalence of chronic pain in the United States in 2016. From the analysis, 20.40% of the patients had chronic pain and 8% had a high-impact chronic pain. [5]

 

As a form of treatment, neuromodulation can offer relief to the patient by providing electrical or chemical stimulus to the nervous system with the purpose of treating chronic pain6 multiple sclerosis, trigeminal neuralgia 7, epilepsy, while also useful for visual, auditive, or psychiatric alterations8.

Within the structures of the central nervous system, white matter and the cerebrospinal fluid are the ones that presents the greatest electrical conductivity9. Other structures, such as gray matter, bone, and epidural fat, have minimal conductive capabilities. The electrical current produced by the electrical contacts flows from the electrode to the cerebrospinal fluid and the dorsal root of the spinal cord.

Neuromodulation basically works by modulating the neuronal information created by pain that is mostly transmitted by the dorsal roots of the spinal cord.

There are several neuromodulation techniques10, such as:

  • Transcutaneous and peripheral nerve stimulation
  • Spinal cord stimulation
  • Repetitive transcranial magnetic stimulation
  • Deep brain stimulation
  • Motor cortex stimulation

Escalation of Pain Treatment 

Pain is the most frequent reason for a medical consult, according to a study published in the Sao Paulo Medical Journal. 11

 

Figure 2 - Shows the reasons for seeking consultations at the primary care units
Figure 2 – Shows the reasons for seeking consultations at the primary care units. Pain was the most commonly reported complaint after the study with 478 patients. The kinds of pain reported by patients were as follows, in frequency order: musculoskeletal pain (15.7%; 75/478); headache (10.4%; 50/478); abdominal pain (8%; 38/478); and chest pain (1.1%; 5/478). The most frequent types of musculoskeletal pain were back pain (33%) and joint pain (33%). [12]

 

In order to perceive pain, we require a sensitive neural network and afferent pathways that can respond to nociceptive stimuli; a process that can also be influenced by psychological factors. 13 It may seem counterintuitive, but personality traits can highly influence our pain threshold. Psychologists point to 2 components at work:

  • Cognition & evaluation: that is to say, the thoughts, anticipations, and predisposition of the person when faced with pain.
  • Subjective & emotional: identifying and managing emotions that may arise when in pain, since they can interfere in the calibration of perceived painful sensations.

Norms of use of the analgesic ladder exist as a guide for the management of administering pain-relieving drugs 14. The analgesic ladder describes 3 steps of painkiller administration, with each involving a subset of analgesics:

In the first step, pain appears, wherein the order of analgesics to be considered should be:

  • Non-opioid – NSAIDs, such as paracetamol, ibuprofen, naproxen, etc.
  • Adjuvants*

*Note: Adjuvants can be pharmacological, for example, anticonvulsants (gabapentin, carbamazepine), steroids (corticosteroids), anxiolytics/hypnotics (clonazepam, alprazolam), antidepressants (amitriptyline, nortriptyline), etc., which are not made to treat pain specifically, but can enhance pain-relieving effects when used in combination with actual analgesics. Adjuvants can also be non-pharmacological, for example, acupuncture and physical therapy.15

If pain does not subside, or if it worsens, the patient has reached the second step of analgesic treatment:

  • Mild to moderate pain opioids – such as codeine, tramadol, propoxyphene.16
  • Non-opioid (see above)
  • Adjuvant (see above)14

     

After attempting the class of analgesics of the above 1st and 2nd step and pain has not subsided, or has worsened, we have reached the third step of the analgesic ladder:

  • Moderate to severe pain opioids – a few examples are morphine, fentanyl, buprenorphine, and methadone.17
  • Non-opioid (see above)
  • Adjuvant (see above)

A higher step in the ladder depends on the failure of the previous step. If the patient does not show improvement, the above potent opioids could be recommended.

Treating chronic pain can also be assisted by interventional therapies as well, these include patient-controlled anesthesia (PCA) therapy, nerve block injections, and spinal cord stimulation (includes neuromodulation), among others.

Neuromodulation offers a control strategy for severe pain, or as an alternative to other minor invasive therapies that haven’t favored the patient. For example, clinical use of electrical spinal cord stimulation (SCS) is justified by the theory postulated by Melzack and Wall in 1965, and is referred to as the ‘gate control theory’18, which states that pain sensation can be shutoff by the activation of afferent nerve fibers in charge of inhibiting the transmission of nociceptive information to the brain by applying electrical stimulus to the site of interest.19 Using electrical stimulation as a form of neuromodulation helps treat the clinical manifestations that present severe focal neuropathic pain19. The neural mechanisms that would allow an understanding of the action of electrical stimulation on nerves with regards to pain are not completely clear. However, experimental studies have observed a suppressive effect of electrical stimulation in tactile allodynia, which is mediated by Aa fibers, and represent a state of central hyperexcitability.20 According to the Royal North Shore Hospital’s pain specialist Dr. Charles Brooker in an interview with ABC News, “Spinal cord stimulators have been around for 20 to 30 years, which involve a wire sitting just outside the spinal cord, connected to a battery with a computer, just like a pacemaker really. It sends signals into the spinal cord and so the person with pain feels tingling in the pain area and that confuses the brain and they don’t feel the pain, they just feel a pleasant tingling sensation.”21

The procedure is done in 2 phases, the SCS trial procedure and the SCS permanent implantation. During the former, one or more electrodes are placed at the site(s) of interest just to see how the patient responds to the setup. If all goes well, the medical team will proceed towards permanent implantation and internalization of the electrical generator system, the site of which depends on the pathology that is causing the pain.  

The most difficult part of the procedure is the insertion of the electrode. This is because the efficiency SCS depends on its correct placement. The electrode is left implanted inside the epidural space, wherein paresthesia replaces perceived pain upon electrical stimulation.

SCS is indicated in the treatment of moderate to severe chronic pain 22 that are secondary to focal neuropathies, who are in turn secondary to:

  • Dejerine-Roussy Syndrome22
  • Radiculopathies24
  • Grade 3 and grade 4 angina pectoris.
  • Post laminectomy syndrome25
  • Type 1 or type 2 complex regional pain syndrome26
  • Phantom limb pain27
  • Myelopathy 28
  • Pain by severe ischemia (in the extremities) of varied etiology, such as Buerger’s disease, Raynaud’s syndrome, or chronic obliterative arteriopathy.

The system is comprised of implantable electrodes and an electrical generator that can be external (programmed) or internal. The electrode is implanted in the epidural space, which is generally accessed via percutaneous puncture, where it’s ascended to the desired level by a fluoroscopic guide29. “It is important to note that the stimulation does not eliminate the source of the pain; instead, it changes the signal to the brain, changing the feeling of pain to more of a tingling sensation. The brain and spinal cord can understand different types of pain, such as hot, cold, sharp, dull or vibrational. However, even though the brain and spine can understand an untold number of those types of pain, they can only experience one type at a time,” said Dr. C. Lan Fotopoulos, board-certified in Physical Medicine and Rehabilitations, Pain Medicine, Sports Medicine and Undersea Hyperbaric Medicine, currently practicing medicine at Dickson-Diveley Orthopedics. 30

Complications

Treatment by SCS is considered very safe and the rates of complications are very low. Mortality associated with electrical implantations is virtually non-existent. Complications include electrode migration (the most common) and fracture, early battery depletion, hardware malfunction, and infection.31

 

Figure 3 - Shows the percentage of the most common complications of spinal cord stimulation [33]
Figure 3 – Shows the percentage of the most common complications of spinal cord stimulation. In a 20-year review of the literature, it was concluded that the most common complications of SCS included lead migration (13.2%), lead breakage (9.2%), infection (3.4%), hardware malfunction (2.9%), and unwanted stimulation (2.4%). [33]
Figure 4- Shows the percentage of patients who suffer from complications after all patients received a surgically implanted paddle-type electrode
Figure 4- Shows the percentage of patients who suffer from complications after all patients received a surgically implanted paddle-type electrode. From the 212 patients on the study, 74 (35%) patients experienced complications, of which 57% were benign, while 42% required invasive treatment. Most frequent complications (n=22, 10%) were hardware malfunctions. There were two cases (0.9%) of postoperative neurological deficit and nine (4.2%) with postoperative infections.[33]

“This is a reversible, minimally invasive procedure.  It’s nondestructive, compared with neuro-ablation; it reduces the abuse of narcotics; and it can improve a patient’s ability to perform activities of daily living,” said Dr. Allan L. Brook, director of Neuro-interventional Neuroradiology at Montefiore Medical Center in the Bronx, N.Y.34

Although there are some difficulties in interpreting long-term consequences, there are studies that show their effectiveness against refractory angina pectoris, complex regional pain syndrome, and critical limb ischemia, arachnoiditis, peripheral vascular disease, and multiple sclerosis, among others.35 

Extraspinal Implants

These include cervical-occipital (C1-C3) nerve stimulation, peripheral nerve stimulation (transcutaneous electrical nerve stimulation, or TENS), and motor cortex stimulation.  They’ve proven excellent options for patients with cranial neuralgias, fibromyalgia, headache disorders (migraines, cluster headaches), and cutaneous neuralgias.36 

On occasion, SCS presents limitations as a solution to some types of neuropathic pain in the head and neck. These limitations are sometimes due to the painful affectation of an extensive surface area on the body, as is the case in thalamic pains. Also, some painful processes prove to be stubborn in responding to analgesics, like in torn plexus cases. To help resolve these issues, Tsubokawa et al., presented the treatment results of certain types of neuropathic pain from electrical stimulation of the prefrontal motor cortex. Its usefulness in patients with neuropathic pain has been verified when it’s secondary to:37 

  • Trigeminal neuropathy
  • Pain after suffering from a stroke
  • Brachial plexus avulsion
  • Multiple sclerosis pain
  • Wallenberg syndrome
  • Phantom limb pain
  • Postherpetic neuralgia

In terms of complications, seizures might be common since the motor cortex is being stimulated in a direct fashion, according to studies on rats. 38 Other complications include infection and hemorrhaging. 39

Once the electrode is in place, stimulation is performed until the point of threshold for motor response. It is during this phase in which convulsions related to stimulus may appear, so it’s important to be prepared for such an event. What follows is a test period of a few weeks with an external stimulator. If the analgesic response is beneficial enough, the next step is the permanent implantation of a generator with similar electrical parameters. Just like in SCS, there are patients who require continuous electrical stimulation to offset pain, while others may need it intermittently.

Neuromodulation has experienced innovative improvements as an alternative to usual strategies of chronic pain treatment, particularly when other treatment methods have not proven satisfactory. Furthermore, the procedure is reversible. Still, continuous improvement in the field of neuromodulation is crucial in minimizing or altogether avoiding any complications.

References:

  1. Matthew D, et al. Neuromodulation for Brain Disorders: Challenges and Opportunities (IEEE Trans Biomed Eng. 2013) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724171/
  2. Rolf Detlef Treede, et al. A Classification of Chronic Pain for ICD-11 (Journal of Pain, June 2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4450869/
  3. World Health Organization, ICD-11 Mortality and Morbidity Statistics (December, 2018) https://icd.who.int/browse11/l-m/en
  4. James Dahlhamer, PhD, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016 (Centers for Disease Control and Prevention/Morbidity and Mortality Weekly Report) https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.htm?s_cid=mm6736a2_w#T1_down
  5. James Dahlhamer, PhD, et al. Prevalence of Chronic Pain and High-Impact Chronic Pain Among Adults — United States, 2016 (Centers for Disease Control and Prevention/Morbidity and Mortality Weekly Report) https://www.cdc.gov/mmwr/volumes/67/wr/mm6736a2.htm?s_cid=mm6736a2_w#T1_down
  6. Jensen MP, et al. Neuromodulatory treatments for chronic pain: efficacy and mechanisms (Nature Reviews, Neurology, March 2014) https://www.ncbi.nlm.nih.gov/pubmed/24535464
  7. Abboud H, et al. Neuromodulation in multiple sclerosis (Mult Scler. 2017) https://www.ncbi.nlm.nih.gov/pubmed/29115915
  8. Temel Y, et al. Neuromodulation in psychiatric disorders (Int Rev Neurobiol. 2012) https://www.ncbi.nlm.nih.gov/pubmed/23206687
  9. De Andres, J & Reina, Miguel & Hernández-García, José & Carrera, A & Oliva, A & Prats-Galino, Alberto. (2011). ROLE OF SPINAL ANATOMICAL STRUCTURES FOR NEUROMODULATION. Regional Anesthesia and Pain Medicine. E130, https://www.researchgate.net/publication/265377023_ROLE_OF_SPINAL_ANATOMICAL_STRUCTURES_FOR_NEUROMODULATION
  10. Rokyta, et al. Neurostimulation methods in the treatment of chronic pain (Physiol. Res. 61 (Suppl. 2): S23-S31, 2012 April, 2012) https://pdfs.semanticscholar.org/09ca/4e91ab219f12c283bb15d221fb103b89900d.pdf
  11. Rinailda de Cascia Santos Torres, et al. Main reasons for medical consultations in family healthcare units in the city of Recife, Brazil: a cross-sectional study (Sao Paulo Medical Journal, 2015) http://dx.doi.org/10.1590/1516-3180.2014.9490902
  12. Steven J. Linton, William S. Shaw. Impact of Psychological Factors in the Experience of Pain (Physical Therapy, 2011) https://doi.org/10.2522/ptj.20100330
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  14. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses (Geneva, World Health Organization; 2012), https://www.ncbi.nlm.nih.gov/books/NBK138349/
  15. Cherian Varghese, et al., Manual for Palliative Care (Ministry of Health and Welfare, Government of India, 2005) http://www.searo.who.int/india/topics/cancer/Cancer_resource_Manual_5_Palliative_Care.pdf
  16. Wojciech Leppert, Pain Management in Patients with Cancer: Focus on Opioid Analgesics (Current Pain Headache Report, 2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3130126/
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  18. Joel Katz, PhD, et.al. The Golden Anniversary of Melzack and Wall’s gate control theory of pain: Celebrating 50 years of pain research and management (Pain Research and Management Journal, November 2015) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676495/
  19. Nick Christelis. Neuropathy, Neuropathic Pain, and Painful Peripheral Neuropathy (International Neuromodulation Society, 2017) https://www.neuromodulation.com/fact_sheet_painful_peripheral_neuropathy
  20. Clifford J Woolf. Central Sensitization: Implications for the Diagnosis and Treatment of Pain (Pain, March 2011) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268359/
  21. Lindy Kerin. Patient fitted with world-first spinal cord stimulator to treat chronic pain at Royal North Shore Hospital (ABC News, 2015) https://www.abc.net.au/news/2015-10-15/patient-fitted-with-spinal-cord-stimulator-to-treat-chronic-pain/6856792
  22. Young Hoon Jeon, MD. Spinal Cord Stimulation in Pain Management: A Review (Korean J Pain. 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389317/
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  24. Kelsey JL. Epidemiology of radiculopathies (Adv Neurol. 1978) https://www.ncbi.nlm.nih.gov/pubmed/369327
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  26. En Lin Goh, et al. Complex regional pain syndrome: a recent update (Burns Trauma. 2017) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5244710/
  27. Nikolajsen  T. S. Jensen. Phantom limb pain (BJA: British Journal of Anaesthesia, 2001) https://academic.oup.com/bja/article/87/1/107/304236
  28. J. Seidenwurm. Myelopathy (American Journal of Neuroradiology, 2008) http://www.ajnr.org/content/29/5/1032
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  30. Ann Butenas. Spinal Cord Stimulation… A Proven Procedure To Greatly Reduce Chronic Back Pain (Healthy Kansas City, 2018) http://healthykcmag.com/spinal-cord-stimulation/
  31. Bendersky D., et al. Is spinal cord stimulation safe? A review of its complications (World Neurosurgery, December 2014)   https://www.ncbi.nlm.nih.gov/pubmed/23851231
  32. Frank W. Petraglia, III, BS, et al. The Incidence of Spinal Cord Injury in Implantation of Percutaneous and Paddle Electrodes for Spinal Cord Stimulation (Neuromodulation. 2016) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4724311/
  33. Kleiber JC, et al. Is spinal cord stimulation safe? A review of 13 years of implantations and complications (Rev Neurol, Paris. 2016) https://www.ncbi.nlm.nih.gov/pubmed/27776893 
  34. James Coe (MD,PhD). Spinal Cord Stimulation An Option For Chronic Pain (Oruen) https://www.oruen.com/neurology/pain/spinal-cord-stimulation-an-option-for-chronic-pain
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  37. Guillermo Monsalve, Motor Cortex Stimulation for Facial Chronic Neuropathic Pain: A Review of the literature (Surgical Neurology International, 2012) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3348447/
  38. Harreby KR, et al. The effect of spinal cord stimulation on seizure susceptibility in rats (Neuromodulation. 2011) https://www.ncbi.nlm.nih.gov/pubmed/21992196
  39. Dylan Henssen et al., Long term effects of motor cortex stimulation in patients suffering from neuropathic pain: An observational study (Public Library of Science Journal, January 2018) https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0191774

 

Robert Velasquez
28 July, 2019

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Hello everyone, my name is Robert Velazquez. I am a content marketer currently focused on the medical supply industry. I studied Medicine for 5 years. I have interacted with many patients and learned a lot...read more:

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