Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome

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Research question: What is the evidence for the efficacy of dorsal root ganglion stimulation for complex regional pain syndrome? How do the clinical outcomes compare to less invasive and lower cost options?

Date: 19/9/2022

Requestor: Lynette redacted: s22(1)(a)(ii)-irrelevant material

Endorsed by (EL1 or above): Andrearedacted: s22(1)(a)(ii)-irrelevant material

Researcher: Stephanie redacted: s22(1)(a)(ii)-irrelevant material

Cleared by: Stephanieredacted: s22(1)(a)(ii)-irrelevant material

1. Contents

Dorsal Root Ganglion Stimulation for Complex Regional Pain Syndrome …………………………… 1

1. Contents ………………………………………………………………………………………………………….. 1

2. Summary …………………………………………………………………………………………………………. 2

3. Background ……………………………………………………………………………………………………… 2

3.1 What is complex regional pain syndrome? …………………………………………. 2

3.2 What is dorsal root ganglion stimulation? …………………………………………. 3

4. What is the evidence for the efficacy of dorsal root ganglion stimulation? …………….. 4

4.1 Literature review for efficacy of dorsal root ganglion stimulation …………….. 4

4.2 Recommendations for use of dorsal root ganglion stimulation …………….. 5

5. Alternative treatments to DRG stimulation for CRPS ……………………………………………… 7

6. References ………………………………………………………………………………………………….. 10

2. Summary

Complex regional pain syndrome can develop after direct trauma to a limb. Most cases of complex regional pain syndrome will resolve over a few months, however some individuals may experience long-term pain and disability.

Dorsal root ganglion stimulation is one treatment option for complex regional pain syndrome. The efficacy of dorsal root ganglion stimulation appears superior to other neuromodulation techniques such as spinal cord stimulation, however it should be considered one of the last management options after all other pain management techniques have been attempted and failed.

3. Background

3.1 What is complex regional pain syndrome?

Complex regional pain syndrome (CRPS) is characterised by neuropathic pain that typically affects an extremity and develops after direct physical trauma (Pilgrim and Schiebel, 2017). While many cases are mild, in some people the pain can be disproportionately severe compared to the triggering event, with these patients reporting a very low quality of life (Pilgrim and Schiebel, 2017).

Common symptoms of CRPS include (Better Health Channel, 2015; National Institute of Neurological Disorders and Stroke (NINDS), 2020; Pilgrim and Schiebel, 2017):

• Unprovoked or spontaneous pain (e.g., squeezing, burning or pins and needles sensation) that can be constant or fluctuate with activity
• Excess or prolonged pain after use or contact
• Changes in skin temperature, colour or swelling of the limb
• Changes in skin texture
• Abnormal sweating and nail and hair growth
• Stiffness in affected joints
• Wasting away or excess bone growth
• Loss of fine motor control, tremors, spasms or impaired muscle strength due to pain and abnormalities in sensory input that coordinates movement
• Limited range of motion.

CRPS is divided into two subtypes depending on whether nerve damage is present. CRPS I (previously known as reflex sympathetic dystrophy) has no clinically apparent nerve damage, whereas CRPS II (previously called causalgia) has confirmed nerve damage (Pilgrim and Schiebel, 2017).

The exact cause of CRPS is unknown, but NINDS (2020) suggest up to 90% of cases are triggered by nerve trauma or injury to the affected limb that damages the thin sensory and autonomic nerve fibres. It is believed this leads to dysfunction of the sympathetic nervous system and induces an inflammatory response that causes blood vessels to spasm, leading to swelling and pain (NINDS, 2020; Pilgrim and Schiebel, 2017). Injuries that can lead to CRPS include blunt trauma, lacerations, burns, frostbite, fractures and casting, sprains and strains, and surgery-related injury such as knee arthroscopy or carpel tunnel surgery (Better Health Channel, 2015; NINDS, 2020; Pilgrim and Schiebel, 2017).

CRPS only develops in limbs because circulation in extremities is limited. Damage to nerve fibres can compromise vascular flow, impeding delivery of oxygen and nutrients needed for healing (NINDS, 2020). Additionally, conditions such as diabetes or exposure to nerve toxins can make the nerves more vulnerable to damage. The immune system and genetics have also been implicated in some cases (NINDS, 2020).

CRPS is more common in women, reportedly up to three times more likely to be affected than males (Better Health Channel, 2015). The mean age of onset is 36-46 years, however the condition can occur in anyone at any age (Pilgrim and Schiebel, 2017). CRPS is rare in the elderly who have less inflammation after injury, and in young children who heal very quickly and completely (NINDS, 2020). The outcome of CRPS is variable, but most often people experience mild symptoms over a few months as the injured nerve heals (NINDS, 2020). In rare circumstances, some individuals may experience prolonged severe pain and disability despite treatment (Better Health Channel, 2015; NINDS, 2020).

3.2 What is dorsal root ganglion stimulation?

Dorsal root ganglions (DRG) are at each segment level of the spinal cord and lumbosacral spine, laying in the intervertebral foramina where the nerve roots exit the spinal column (Nagpal et al, 2020). They are the first cell body of the sensory pathway from the periphery to the central nervous system (Nagpal et al, 2020). The DRG may have a role in chronic neuropathic pain through hyperexcitability and spontaneous, ectopic firing after peripheral nerve injury as is seen in CRPS I and II and other peripheral nerve injuries (Deer et al, 2019; Nagpal et al, 2020).

Neurostimulation is the application of electricity to the nervous system to achieve a desired therapeutic response, and neurostimulation of the DRG as an interventional treatment for chronic pain was approved in Europe in 2011 and the United States in 2016 (Deer et al, 2019). The DRG is considered an important target for treating neuropathic pain because it transmits sensory input from the peripheral to central nervous system (Deer et al, 2019). DRG stimulation is thought to provide more precise focal coverage of pain as physicians rely on

patient’s descriptions of pain distribution patterns to determine lead placement compared to spinal cord stimulation (Deer et al, 2019; Nagpal et al, 2020). As the DRG lays in the epidural space it is amenable to epidural access techniques allowing device leads to be safely implanted (Deer et al, 2019). After a trial period, if DRG stimulation appears to be successful in the reduction of pain and other symptoms, an implantable pulse generator can be placed subcutaneously.

4. What is the evidence for the efficacy of dorsal root ganglion stimulation?

4.1 Literature review for efficacy of dorsal root ganglion stimulation

The primary outcome for DRG stimulation in most studies is a ≥50% reduction in pain, with secondary outcomes relating to concerns such as physical function, mood, quality of life, opioid use and complications (Nagpal et al, 2020).

Results from a systematic literature review (Deer et al., 2020) into the efficacy of DRG stimulation for CRPS or chronic neuropathic pain analysed one randomised control trial and five prospective observational studies and reported:

• Deer et al. (2017): randomised control trial, N = 76 – over 80% of participants who had a DRG stimulation device implanted experienced greater than 50% reduction in pain three months after the procedure and 74% at 12 months. The reported relief in pain by the DRG stimulation group was superior to the comparison group who received spinal cord stimulation
• Huygen et al. (2018): observational, N = 12 – more than half reported 50% or better pain relief, and the overall average pain relief was 46% at 12 months; improved mood and quality of life was demonstrated
• Morgalla et al. (2018): observational, N = 62 – 78% experienced pain reduction at 12 months, 65% at 36 months
• Van Buyten et al. (2015): observational, 8 received implanted device – at 1-month post-procedure the average pain level decreased 62% compared to baseline, at 12 months the overall pain relief was 62% with five participants reporting greater or equal to 50% pain relief. One participant had the device extracted due to unsatisfactory pain relief.
• Liem et al. (2015): observational, 32 received implanted device – at the 12 month follow up 25 participants reported a 56% decrease in pain from baseline levels. Reported quality of life improved and total mood disturbance scores decreased
• Deer et al. (2013): observational, 8 participants provided data for efficacy – 75% experienced reduction in pain at 4 weeks. No further follow up reported.

Multiple case-series observational studies are noted. One particular study, Yang and Hunter (2017), reports the experience of two patients with lower extremity CRPS who had failed a tonic spinal cord stimulation device so proceeded to a DRG stimulation trial. One patient reported a 90% reduction in pain and improvement in gait during the trial so had the spinal cord stimulation device explanted in favour of the DRG stimulator. The second patient had the DRG stimulation device ‘piggy back’ with the spinal cord stimulation device to trial the technology and reported an immediate improvement in pain; when only the DRG stimulation device was active the pain score was at its lowest. At 8 months both participants had retained the improvement in function and pain relief.

Limitations in the literature noted by Nagpal et al. (2020) and Potter et al. (2022) include the conflict of interest as some studies are funded by industry providers (e.g., St Jude Medical, Spinal Modulation) increasing the risk of bias, limited long term follow up data, and many papers include the same authors so there is a concern some studies have used the same cohort of participants. Finally, the lack of randomised control trials makes it unclear whether the findings are robust and reproducible.

4.2 Recommendations for use of dorsal root ganglion stimulation

The Food and Drug Administration approved dorsal root ganglion stimulation in 2016 (Potter et al, 2022). No information could be found regarding approval by the Therapeutic Goods Administration.

A 2018 literature review by the Neuromodulation Appropriateness Consensus Committee found there was strong evidence for the use of DRG stimulation for patients with CRPS I and II and other chronic pain syndromes of the pelvis and lower extremity (Nagpal et al, 2020). The evidence quality was considered to be level II (based on one randomised control trial and two observational studies) by the committee and was used to provide recommendations around the used of DRG stimulation for different pain conditions (Deer et al., 2019):

• General considerations for patient selection –

  o Be psychologically stable

  o Have a defined pathology

  o Have any issues with addiction under control

  o Have satisfactory anticoagulation management that allows for the safe placement of an epidural lead

  o Have no unaddressed or poorly managed medical conditions that may impact the outcome of the procedure, such as those that relate to infection risk, diabetes, or other systemic disease

  o Have satisfactory access to the target foramen, i.e., no stenosis

  o Be well informed on the device and treatment, having the chance to ask

questions and be offered other options

• Complex regional pain syndrome

  o Based on the one randomised control trial available, the committee recommended DRG stimulation as effective therapy for treatment of CRPS type I or type II of the lower extremity. The trial compare DRG stimulation to tonic spinal cord stimulation, 81.2% of participants who received DRG stimulation achived > 50% pain reduction compared to 55.7% in the other group. This resulted in improved quality of life and psychological disposition, less postural interference from stimulation or parasthesia compared to tonic spinal cord stimulation.

  o The committee recommended further research for DRG stimulation of the upper extremity for CRPS treatment of type I or type II.

• Diabetic peripheral neuropathy

  o There is stronger evidence of efficacy for spinal cord stimulation than DRG stimulation. Due to the limited data regarding efficacy, DRG stimulation should be carefully justified.

• Other peripheral neuropathies

  o More evidence is required before DRG stimulation can be recommended for non-diabetic peripheral neuropathy

• Postsurgical pain

  o There is reportedly a good response to DRG stimulation in patients with post-surgical pain after thoracotomy or mastectomy.

  o The committee recommend use of DRG stimulation in patients with chronic postoperative surgical pain, however decisions should be made on a case-by-case basis (moderate consensus within the committee).

• Pelvic pain

  o Pelvic pain is a non-specific term representing a variety of pathologies that can arise from many causes, such as: pudendal neuralgia, interstitial cystitis, endometriosis, vulvodynia, ilioinguinal neuralgia. Pelvic visceral pain arising from S2, S3 and S4 need to be differentiated from groin pain mediated by T12 and L1. Spinal cord stimulation has only a fair response, with 33% of patients explanting the technology due to loss of therapeutic effect. Additional studies are required to determine the efficacy of DRG stimulation for pelvic pain.

  o The committee recommendation is that DRG stimulation only be used according to strict criteria for pelvic pain, including identification of the

mechanism of injury (surgical or trauma) and related pathology, along with the designation of visceral or somatic. Proceeding with DRG stimulation should be done within a medical team, including a gynaecologist, urologist and psychologist. Patients with significant psychology issues should be excluded or treated prior to DRG stimulation.

• Groin pain

  o Based on a study of 25 patients who had successful trial and proceeded with implantation, the average rating of pain relief achieved was 71% for over 80% of the cohort. Therefore, DRG stimulation is recommended for the treatment of neuropathic groin pain

• Phantom limb and stump pain

  o Further study is needed for patients with phantom limb pain.

• Postherpetic neuralgia

  o The committee advised that DRG stimulation has better evidence than spinal cord stimulation for this condition, but no formal recommendation was listed. It was noted that the level of lead placement for best results was being discussed, therefore further research is needed before the procedure could be recommended.

5. Alternative treatments to DRG stimulation for CRPS

There is no single recommended treatment for CRPS, with the primary goal of treatment being to restore movement and function of the affected limb (Better Health Channel, 2015). CRPS has a broad range of symptoms therefore patients may require management from different clinical specialists, including orthopeadic surgeons, anaesthetists, rheumatologists and rehabilitation specialists (Goh et al, 2017). Treatment is most effective when started early after onset (NINDS, 2020).

Physical and occupational therapy is a key component of rehabilitation for patients with CRPS and is recommended as the first-line treatment (Goh et al, 2017). NINDS (2020) indicate rehabilitation and physical therapy are the single most important treatment for CRPS. Initial strategies to reduce swelling and pain are key to participation in movement therapy (Better Health Channel, 2015). Patients can develop kinesophobia, so therapy is designed to overcome this fear to enable the patient to gain the best use of the limb. Physical and occupational therapy should be individualised to the patient needs, but may include elevation, massage, contrast baths, transcutaneous electrical nerve stimulation, gentle range of motion, isometric strengthening exercise and stress loading of the affected limb along with sufficient analgesia (Goh et al, 2017). An occupational therapist will encourage use of the affected limb in activities of daily living (NINDS, 2020). Specialised garments may reduce oedema and sensory overload of the affected limb (Goh et al, 2017). No time frame was found in the literature regarding when physical or occupational therapy should be ceased, however it was

noted that ongoing rehabilitation can help prevent or reverse secondary spinal cord and brain changes associated with disuse and chronic pain (NINDS, 2020).

Psychological therapy may be warranted for people who suffer a significant impact on their health-related quality of life. People with CRPS may develop secondary depression, situational anxiety and sometimes post-traumatic stress disorder (NINDS, 2020). This may include cognitive behaviour therapy, relaxation skills and biofeedback to facilitate rehabilitation and decrease the intensity of pain (Better Health Channel, 2015; Goh et al, 2017).

Medical management includes corticosteroids and non-steroidal anti-inflammatory drugs to reduce inflammation. However there is evidence these medications do not alleviate symptoms for all patients (Goh et al, 2017). Other medical options include opioid use, but this is more useful in the acute phase of the disorder (Goh et al, 2017). Better Health Channel (2015) indicates medications prescribed for epilepsy or depression can sometimes help manage CRPS, however Goh et al (2017) indicated the long-term efficacy of these drugs was not well researched. NINDS (2020) note that medical management is more effective when taken early in the course of the disorder.

Analgesia therapy includes use of a sympathetic blockade to alleviate sympathetically mediated pain and can be used in combination with botulinum toxin to prolong the effect of the analgesia (Goh et al, 2017). The most commonly used is a sympathetic ganglion block, which involves the use of local anaesthetic to stop some of the nerves in the affected limb from functioning (Better Health Channel, 2015). There is evidence this treatment can provide substantial pain relief and improve functional use, however there is less information about long term effect on CRPS (Goh et al, 2017).

Non-invasive neural stimulation includes repetitive transcranial magnetic stimulation (rTMS) and transcranial direct electrical stimulation (NINDS, 2020). These methods are still being investigated, however a meta-analysis (including one randomised controlled trial and two prospective observational studies) by Chang et al (2020) suggests that while there was not an immediate reduction in pain after one rTMS session, pain was significantly reduced one week post-completion of the entire schedule (5-10 sessions) of rTMS therapy.

Surgical options include neuromodulation, sympathectomy or amputation. Patients who are not responsive to sympathetic blockade may be suitable for neuromodulation to treat CRPS (Goh et al, 2017). A randomised controlled trial cited in Goh et al (2017) reports that spinal cord stimulation and physiotherapy may be more effective at pain relief compared to physiotherapy on its own at 6 months and 2 years follow up. It was noted, though, that effectiveness diminished at the long-term follow up of 5 years. As noted above, DRG stimulation appears to be more effective than spinal cord stimulation for the relief of pain in patients with CRPS. Side effects of having the spinal cord stimulation device implanted, which would be similar for DRG stimulation, include lead displacement, pulse-generator pocket revision, pulse-generator failure and infection (Goh et al, 2017). Better Health Channel (2015) suggests that device implant-therapy should be considered a last resort when all other pain management techniques have failed.

Sympathectomy may be done as an extension of temporary sympathetic blockade in patients who experience satisfactory but transient relief from sympathetic block (Goh et al, 2017). A sympathectomy involves severing the sympathetic chains using chemicals, radiofrequency or

open surgical techniques to prolong analgesia. Chemical sympathectomy may use alcohol or phenyl injections but there is limited evidence to support effectiveness (Goh et al, 2017). Radiofrequency provides a long-lasting pain relief, with 40% patients reporting greater than 50% pain reduction after one year. Complications from sympathectomy are common and include post-sympathectomy neuralgia, anhydrosis (inability to sweat/perspire) and Horner’s syndrome (neurological condition affecting the face and eye on one side of the body) (Goh et al, 2017). Therefore this treatment is only considered when all alternative treatment options have failed (Goh et al, 2017; NINDS, 2020).

Amputation may be indicated due to pain, limb dysfunction, gangrene, infections or ulcers. While most patients report relief in pain following amputation, others may experience phantom pain and recurrence in the residual limb (Goh et al, 2017). This should only be performed after consultation from several specialists and psychological counselling (NINDS, 2020).

6. References

Better Health Channel. (2015). Complex regional pain syndrome (CRPS). Department of Health, State Government of Victoria. Accessed from https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/complex-regional-pain-syndrome-crps

Chang, M. C., Kwak, S. G., & Park, D. (2020). The effect of rTMS in the management of pain associated with CRPS. Translational neuroscience, 11(1), 363–370. https://doi.org/10.1515/tnsci-2020-0120

Deer, T. R., Grigsby, E., Weiner, R. L., Wilcosky, B., & Kramer, J. M. (2013). A prospective study of dorsal root ganglion stimulation for the relief of chronic pain. Neuromodulation : journal of the International Neuromodulation Society, 16(1), 67–72. https://doi.org/10.1111/ner.12013

Deer, T.R., Levy, R.M., Kramer, J., et al. Dorsal root ganglion stimulation yielded higher treatment success rate for complex regional pain syndrome and causalgia at 3 and 12 months: A randomized comparative trial. Pain, 158(4), 669–81.

Deer, T. R., Pope, J. E., Lamer, T. J., Grider, J. S., Provenzano, D., Lubenow, T. R., FitzGerald, J. J., Hunter, C., Falowski, S., Sayed, D., Baranidharan, G., Patel, N. K., Davis, T., Green, A., Pajuelo, A., Epstein, L. J., Harned, M., Liem, L., Christo, P. J., & Chakravarthy, K. (2019). The Neuromodulation Appropriateness Consensus Committee on Best Practices for Dorsal Root Ganglion Stimulation. Neuromodulation, 22(1), 1–35. https://doi.org/10.1111/ner.12845

Goh, E. L., Chidambaram, S., & Ma, D. (2017). Complex regional pain syndrome: a recent update. Burns & Trauma, 5. https://doi.org/10.1186/s41038-016-0066-4

Huygen, F., Liem, L., Cusack, W., & Kramer, J. (2018). Stimulation of the L2-L3 Dorsal Root Ganglia Induces Effective Pain Relief in the Low Back. Pain practice : the official journal of World Institute of Pain, 18(2), 205–213. https://doi.org/10.1111/papr.12591

Liem, L., Russo, M., Huygen, F. J., Van Buyten, J. P., Smet, I., Verrills, P., Cousins, M., Brooker, C., Levy, R., Deer, T., & Kramer, J. (2015). One-year outcomes of spinal cord stimulation of the dorsal root ganglion in the treatment of chronic neuropathic pain. Neuromodulation: journal of the International Neuromodulation Society, 18(1), 41–49. https://doi.org/10.1111/ner.12228

Morgalla, M. H., Fortunato, M., Lepski, G., & Chander, B. S. (2018). Dorsal Root Ganglion Stimulation (DRGS) for the Treatment of Chronic Neuropathic Pain: A Single-Center Study with Long-Term Prospective Results in 62 Cases. Pain physician, 21(4), E377–E387.

Nagpal, A., Clements, N., Duszynski, B., & Boies, B. (2021). The Effectiveness of Dorsal Root Ganglion Neurostimulation for the Treatment of Chronic Pelvic Pain and Chronic

Neuropathic Pain of the Lower Extremity: A Comprehensive Review of the Published Data. Pain Medicine, 22(1), 49–59.

National Institute of Neurological Disorders and Stroke. (2020). Complex regional pain syndrome fact sheet. Accessed from https://www.ninds.nih.gov/complex-regional-pain-syndrome-fact-sheet

Pilgrim, J. R. B. M., & Schiebel, D. F. (2017). Complex Regional Pain Syndrome: an Overview. CINAHL Nursing Guide.

Potter, S. T., Welch, S., Tata, F., Probert, S., & Nagpal, A. (2022). Dorsal Root Ganglion Stimulation. Physical medicine and rehabilitation clinics of North America, 33(2), 359–378.

Van Buyten, J. P., Smet, I., Liem, L., Russo, M., & Huygen, F. (2015). Stimulation of dorsal root ganglia for the management of complex regional pain syndrome: a prospective case series. Pain practice : the official journal of World Institute of Pain, 15(3), 208–216. https://doi.org/10.1111/papr.12170

Yang, A., & Hunter, C. W. (2017). Dorsal Root Ganglion Stimulation as a Salvage Treatment for Complex Regional Pain Syndrome Refractory to Dorsal Column Spinal Cord Stimulation: A Case Series. Neuromodulation, 20(7), 703–707. https://doi.org/10.1111/ner.12622