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15 Articles in Volume 18, Issue #5
Chronic Pelvic Pain: The Need for Earlier Diagnosis and Diverse Treatment
Cross-Linked Hyaluronic Acid for the Management of Neuropathic Pelvic Pain
Fentanyl: Separating Fact from Fiction
Gender Bias and the Ongoing Need to Acknowledge Women’s Pain
Letters to the Editor: 90 MME/day Ceiling; Ehlers-Danlos; Redefining Pain
Post-Menopausal MSK Pain and Quality of Life
PPM Welcomes Dr. Fudin and Dr. Gudin as New Co-Editors
Practitioner as Patient: Understanding Disparities in CRPS
States Take Action to Manage Opioid Addiction
Step-by-Step Injection Technique to Target Endometriosis-Related Neuropathic Pelvic Pain
The Many Gender Gaps in Pain Medicine
The Need for Better Responses to Vulvar Pain
Topical Analgesics for Chronic Pain Conditions
Topical Medications for Common Orofacial Pain Conditions
What’s the safest, effective way to taper a patient off of opioid therapy?

Cross-Linked Hyaluronic Acid for the Management of Neuropathic Pelvic Pain

Case presentation and injection technique targets endometriosis-related pain.

Endometriosis, the presence of endometrial tissue outside of the uterus, is a frequent, estrogen-related condition, affecting approximately 176 million women in the world, or 1 in 10 women between the ages of 15 and 49.1 The condition may lead to infertility in 30 to 50% of those diagnosed,2 as well as multiple types of related pain including: dysmenorrhea, dyspareunia, intestinal and bowel pain, dysuria, and chronic low back and pelvic pain.

The management of endometriosis-related pelvic pain requires medical and, at times, surgical therapy.3 Medical modalities are directed at relieving pain through various mechanisms, including the suppression of: inflammation, cyclical ovarian hormone release, estradiol, and menses. Surgical treatment may be used as a first-line approach or after medical failure. Surgery may consist of a variety of techniques including: fulguration, excision, or ablation of endometrioma implants, as well as resection of rectovaginal nodules, lysis of adhesions and nerve pathways interruption.4 It should be noted that clinical staging of the disease often assists in the selection of treatment in a given case,5 and may include: Stage 1-Minimal, Stage 2-Mild, Stage 3-Moderate, and Stage 4-Severe. The stages are dependent upon the presence, location, extent and severity of endometrial implants, endometriomas, and adhesions.

The following case presents a woman with severe, chronic lumbosacral and pelvic neuropathic pain due to Stage 4 endometriosis-related endometrioma implants, after undergoing multiple surgical interventions that failed to improve her pain control, wherein she is then successfully treated with cross-linked hyaluronic acid (CL-HA). The diagnosis is supported by electromyography (EMG) findings of multilevel lumbosacral radiculopathy6-8 and a negative imaging workup for other causes. The use of CL-HA to treat neuropathic pain was initially presented at the 2015 annual meeting of the American Academy of Pain Medicine.9 This form of treatment is designated as Cross-Linked Neural Matrix Antinociception, or simply XL-NMA.10 CL-HA is made of chemically cross-linked hyaluronic acid – a linear, anionic proteoglycan polysaccharide composed of glucuronic acid and N-acetylglucosamine repeating units.

The Case

A 41-year-old woman, G, P, M, A: 4, 2, 2, 0, presented with persistent, worsening pelvic and low back pain that she described having for 15 years. The pain would intermittently radiate down both lower extremities, right greater than left, and up her lower back. Overall, her pain was worsening; it had persisted daily for the past six years, with localized pain over the anterior and posterior right greater trochanter.

Pain initially began in the right lower quadrant and was attributed to endometriosis in 2000. She had undergone six endometriosis surgeries (most recent was 6 months prior, excisional type, no change). She was status post-appendectomy, complete hysterectomy, with left ovary remaining, lumpectomy for right breast carcinoma (7 years prior) and self-referred to our center for evaluation. Pain interfered with sleep; weight was stable, as was bowel and bladder function. There was dyspareunia due to pain upon penetration. There was no loss of sensation or weakness, but her legs weakened when the pain became severe. She underwent trigger point injections and radiofrequency denervation, three years prior, with no relief.

Her current analgesic regime included:

  • Hydromorphone IR (4 mg; 1 to 1 1/2 tabs, q. 4 to 6 hrs, prn severe pain, as an Oxycodone sparing drug)
  • Oxycodone IR (10 mg; 1 to 1 1/2 tabs, q. 4 to 6 hrs, prn severe pain)
  • Methocarbamol (750 mg; 1 tab, qid, prn muscle spasm).

Self-reported symptoms as shown on Figure 1 revealed pain over the anterior and posterior pelvis, radiating down both lower extremities, anterior and posterior aspects, to just above the knees. The patient noted the pain indicated on the left was referred or radiating from its mirror origin on the right (as shown in Figure 2). She described the pain as: aching, sharp, tight, pulling, and constant. The pain score intensity range was (lowest-average-highest): 3, to 5, to 10/10, aggravated by prolonged sitting, standing, lying, touching, stress, driving and/or riding in a vehicle, vacuuming, and pulling. The patient found some relief from “self-determination,” pain medication, rest, heat, cold, and lying down in a fetal position.

Patient’s Neuropathic Painful Dysesthesias

Right hip and anterior pelvic region:

  • The painful dysesthesias from this region proceeded downward and laterally, anteriorly, and medially.

Right sacral region:

  • The S1, S2 and S4 dysesthesias proceeded horizontally across the buttock, to the anterior pelvis.

  • The S3 dysesthesias, which were the strongest, proceeded in the same direction as the others, but felt deeper, like a level below S1, S2 and S4, and were more intense.

Initial Assessment

Examination: In examining the abdomen/pelvis, there was diffuse tenderness to the lower hemi-abdomen and pelvis, right greater than left, with mild palpation. The vaginal vault was moist, mildly reactively constricted, but admitted two digits. Upon digital pressure superiorly and to the right, right-sided abdomino-pelvic pain was evoked. In assessing the spine, percussion tenderness was noted from L2-3 to S3-4, greatest at L5-S1. The anterior and posterior loading maneuver (ALM/PLM) were both positive at L5-S1. However, the PLM was more severe, with pain noted to the right coxofemoral and greater trochanter region. Palpation over right sacral foramina and greater trochanter revealed additional hyperalgesia and hyperpathia, supporting the presence of neuropathogenicity.

Records review: X-ray of both hips from 3 years prior were noncontributory. A CT Scan of the abdomen/pelvis from two years prior noted previous swelling of the mesentery in the right lower quadrant was not seen, although there was persistent induration in the mesentery (considered: intermittent mesenteric volvulus or internal hernia).

Etiology: Given the patient history, physical assessment, and records, the following differential diagnoses were considered:

  1. Endometriosis related-lumbosacral plexopathy, secondary to radicular implants, with secondary neuropathic pain syndrome
  2. High-lumbar lesion with referred pain to hips/pelvis, with secondary radiculopathy
  3. Intermittent mesenteric volvulus and/or internal hernia, with secondary visceral pain syndrome
  4. Metastatic process due to history right breast cancer (7 years prior), lumpectomy.

New Tests Orders and Results

To refine the above differential diagnoses, several tests were ordered. See Table I for diagnostics and results. Based on the new test results, the following determinations were made:

  1. Probable: endometriosis-related lumbosacral radiculoplexopathy, as suggested by EMG plus secondary neuropathic pain syndrome, with referred pain to hips/pelvis
  2. Not found or resolved: intermittent mesenteric volvulus and/or internal hernia
  3. Not found: metastatic process.

Table 1


To localize potential sites for neuromodulation, the patient was scheduled for differential neural blockade with local anesthetic (lidocaine 2%, plain) at: right dorsal cutaneous nerve branches (see Figure 3) of T11, T12, L1, L2, L3, L4, L5, S1, S2, S3, S4. Note: The left-sided pain areas were not treated as the patient felt that the primary pain generators were on the right, and that those sites were referring pain to the left side. See the step-by-step injection technique here.

Figure 3

With the exception of the anterior pelvic region (see patient commentary), the patient reported good relief and began periodic injections at the same sites, with pain control maintained using an injectate of: 4 cc, 2% plain lidocaine; 7.95 cc, 0.25% plain bupivacaine; and 0.25 mg/0.05 cc, morphine sulfate-MSO4 (5 mg/cc), administering 0.5 to 1.5 cc per site. The patient related that these injections, which provided relief for about 7 days, in combination with her opioids improved substantially her ability to perform daily activities, as well as tend to her children and family, including serving as the primary caregiver of her mother who was undergoing treatment for breast cancer. The patient’s reduction in pain was significant (see Figure 4).


Figure 4

XL-NMA – Neural Matrix Aninociception

Approximately 20 months after the patient first presented to the clinic, she underwent an initial trial of XL-neural matrix antinociception at the same sites, using the same technique, except the volumes of the injectate were reduced to one-tenth of the lidocaine/bupivacaine/MSO4 injectate used (this varied from 0.15 cc to 0.25 cc of cross-linked hyaluronic acid, with a concentration varying from 20 mg/ml (Restylane) to 24 mg/ml (Juvederm) per site.11,12 The patient responded well, with no adverse reactions noted, and achieved a duration of relief of 3 to 4 months for the sacral sites, 4 months for the lumbar sites, and 6.5 months for the greater trochanter region. The patient rated overall improvement after the CL-HA injections at 90%. Change in pain scores was remarkable (see Figure 5).

Figure 5

Since that time, the frequency of injection sessions dropped from three to four times per month on the previous injectate of lidocaine/bupivacaine/morphine, to once every five to six months. There have been no adverse reactions and the patient continues on this regimen to date.

Discussion & Recommendations

While the patient’s outcome using cross-linked hyaluronic acid injections was successful, additional research is necessary to elucidate the mechanism of action of this complex substance, as well as to develop additional techniques for its use in neuropathic pain. In this case, the right anterior pelvic pain was essentially unaffected. Methods such as an intercostal T10-12, transforaminal L1, L2, lumbar sympathetic or celiac XL-NMA may be found to remedy this shortcoming.

Mechanism of Action Summary

Purported mechanisms of action are complex and no doubt, multifactorial.13 Nonetheless, it is possible that the antinociceptive effect may occur in a step-wise fashion over time (ie, immediately or in first 10 minutes after injection) and that the CL-HA acts as a physical shield, thereby forming a protective compartment and blunting spontaneous activity of C fiber and Remak bundle afferency, including aberrant nociceptive ephapse.14 In addition, contemporaneous depolarization of the action potential due to its polyanionic nature and size of its negative charge (a function of its massive molecular size, 500 million daltons to 100 GDa), blocking any transduction of signal, may occur. Its long-term effect may be due to low/high molecular weight mismatch correction resulting in TNFα-stimulated gene 6 protein modulation of the subclinical, regional inflammatory response. Dysregulation at the level of the extracellular neural matrix is stabilized, promoting a restoration of the normal immunoneural cross-talk, thereby negating what is believed to be the root cause for the development of chronic pain.15-18

Furthermore, any injury or insult to the nervous system may cause deafferentation pain (defined as “severe spontaneous pain in body parts distal to the injury despite reduced or no sensitivity to external noxious stimuli to that body part (hypoalgesia or analgesia)”19 as it represents a loss of information from the periphery to the brain. In the case presented, the nerve roots and spinal cord segments of the painful regions in question likely suffered deafferentation and neuropathic pain as a result of injury caused by the endometrial implants. It is this initial injury that likely initiated the cytokine cascade’s proinflammatory, pronociceptive state. For a complete discussion of these mechanisms of action in this regard, see the author’s previous report.13

Overall, this case provides a detailed look at the use and technique of targeted neural matrix antinociception injection of cross-linked hyaluronic acid in the successful treatment of chronic endometriosis pain of the thoraco-lumbar, sacral, and right greater trochanteric region that occurred in a 41-year woman who had previously undergone multiple endometriosis pain related surgeries with no change. The technique presented has resulted in the patient’s enduring pain relief, and proved to be a safe and effective method in this patient (see the Patient's self-reported commentary below). Its routine use should be considered early to manage pain in similar cases.


Patient Commentary

“I was officially diagnosed with severe endometriosis when I was 26 years old. Although, I am very certain it started years before when I was in my teens. My periods where always very heavy flow and extremely painful—painful enough that I would always need a day or two off from school or work. I started taking birth control pills when I was 18 and that seemed to suppress the progression of the disease or at least the symptoms. After I had my first child, when my cycle resumed, the pain returned. My doctor did ultrasounds, MRIs, and x-rays trying to find the cause. She decided to do an exploratory laparoscopy and that’s when they discovered I had severe endometriosis.

Over the next 15 years, I had five more abdominal surgeries. My right ovary was removed, my uterus, my appendix, along with both of my tubes and my cervix because they were covered with the disease. The endometriosis continued to spread and do damage to many nerves in my pelvic area. The nerve damage caused severe pain in my right hip, low back, and my pelvic area.

The pain gradually got worse, increasing from a few days a month to everyday. I was put on countless medications. From pain meds to hormones, birth control pills, IUD and the worst was a medication that shut down my ovaries and put me into medical menopause. I used OTC pain relievers until my stomach couldn’t handle them anymore, as well as ice, heat, and local lidocaine to no avail. Another pain management doctor gave me more medications to try as well as nerve ablation—none of which helped.

The pain was so intense that, most days, I was forced to stay home. I was unable to take care of my home or my children. I was also unable to have sex because it was too painful. When more surgery was no longer an option I began seeking someone to help me deal with the pain. At this point in my life my life quality was terrible. A friend recommended Dr. Campa [the author]. I saw him and he started a treatment plan with the injections. He gave me injections in my right hip, low back and my pelvic area.

Very early in the treatments, I began to feel improvement. The injections would bring my pain scores from a 9 or 10 down to a 2 or 3. The only drawback was that it was short relief. While they were working I was able to start participating in my family life again. I would get the injections once a week. The first three and four days were great but over the next day or two the pain would return. Although while they were working, I could be active and have intercourse that wasn’t painful. The only drawback was that the relief was so temporary.

When Dr. Campa started giving me the cross-linked injections the onset of pain relief was within 24 hours or so. The great thing about them was that they lasted for months not days! Comparing the two different injections, the cross-linked injections brought my pain scores of 9 or 10 to a 1 or 2. Only getting injections every 6 months or so compared to weekly has been so much easier and the time I saved I am able to devote to my family. The long-term pain relief has been an absolute blessing.

Before the cross-link injections, oxycodone and hydromorphone would help minimally with all the nerve pain and abdominal pain from the scar tissue and adhesions. The oral pain medication barely took the edge off of all the pain and I spent most of my time in bed or on the couch unable to move. The cross-link injections brought down my pain levels in my right hip, low back and pelvic area nerves enough that the oral pain medication made the scar tissue and adhesion pain more manageable. I continue to take oxycodone and hydromorphone to help with the severe pain that isn’t nerve related. The scar tissue and adhesion pain is a pulling pain across my whole pelvic region, but the most intense pain originates from the lower right pelvic region. This pain is controlled with opioids, which lowers the pain score from a 9 or 10/ out of 10 to about a 6 out of 10.

In the areas treated with the cross-linked injections, the pain is a least 90% better. The other areas seemed to improve some but it’s hard for me to tell if they actually improved or if they are easier to manage since the other pain is so much better.”

–Commentary provided by the author with patient permission.


Also featured in this special report on Pain Care & Research in Women

Continue Reading:
Step-by-Step Injection Technique to Target Endometriosis-Related Neuropathic Pelvic Pain
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