Fish Oil and BCQ™ as a Novel Treatment Approach to Primary Erythromelalgia: A Case Study

Abstract

Erythromelalgia (EM) is a rare disorder, of which the pathophysiology is poorly understood. Though primary EM is thought to be an autosomal-dominant inherited disorder or of idiopathic origin, secondary EM is associated, most often, with myeloproliferative diseases. Pain management is the primary therapeutic target, however, individual patient responses vary widely, and no single treatment has been determined to be effective.

As such, EM is often associated with reduced quality of life and higher morbidity and mortality. This case study examines an 81-year-old Caucasian female patient with a diagnosis of primary EM, for which previous pharmaceutical therapies had proven ineffective. Therapeutic intervention included a novel, daily supplement regimen of fish oil and BCQ™.

Introduction

Erythromelalgia (EM) is a rare neurovascular syndrome characterized by paroxysmal episodes of erythema, heat, tingling and burning pain in the extremities, which may be aggravated by exercise, stress and increased ambient air temperatures.^1-4 EM is more common in females than males and may develop at any age, however, is most frequently diagnosed in the fifth and sixth decades of life.³ The diagnosis of EM may be made clinically in the presence of five criteria, including burning extremity pain, pain aggravated by warming and relieved by cooling, and erythema and increased temperature of the affected skin.⁵ Ruling out myeloproliferative causes of EM is a top priority of clinical evaluation. Symptoms generally affect the feet, and occasionally the hands and face. Presentation is typically bilateral, although unilateral presentations have also been observed clinically. Patients with EM may seek relief from pain through extreme cooling methods including ice bath immersion, cold sock and glove application, and excessive use of fans. Complications related to hypothermia, frostbite, windburn and ulceration have been reported.^3,6

The etiology of primary EM is through autosomal-dominant inheritance or idiopathic origin, with the idiopathic subtype being most common. The genetic mutation associated with the inherited form of EM has not been documented in idiopathic primary EM and rarely in secondary cases.³

The pathophysiology of primary idiopathic EM is thought to be due to vascular and potentially neurologic abnormalities, resulting in a paradoxical presentation of hypoxia and hyperemia of the affected areas.^1,7 Studies suggest that this is a result of pre-capillary sphincter constriction, with simultaneous opening of arteriovenous shunts, thereby increasing total perfusion of blood with reduced nutrient tissue perfusion. The resulting tissue hypoxia prompts increased local blood flow, which worsens symptoms of erythema, warmth and pain.^7,8 Studies have shown that skin temperature of EM patients in the absence of a flare was lower than control subjects, which further suggests that vasoconstriction may play a role in the pathophysiology of this condition.⁷ It should also be noted that many patients with EM also have small fiber neuropathy, which might explain the effectiveness of certain treatments that address neuropathy in the management of EM.^1,9

EM is a rare condition of which there is no cure and limited data regarding gold standard of care, however pharmaceutical and non-pharmaceutical interventions aim to reduce pain and improve quality of life. Generally, a combination of topical and systemic pharmaceutical agents, as well as non-pharmacologic therapies are employed. Case reports have described use of topical lidocaine and compounded topical amitriptyline and ketamine applied daily to the affected area to be effective in improving pain associated with EM.¹⁰ Aspirin is commonly used in treatment regimens, however, most benefit is seen in those who suffer from EM secondary to a myeloproliferative disease.^11,12 Gabapentin, pregabalin, venlafaxine and oral amitriptyline have all shown success in case reports.^3,13

Non-pharmacologic measures which may help to manage EM include avoidance of triggers, exposure of the affected area to cool water and fans for a short period of time and limb elevation. One case report documented improvement of EM symptoms with high doses of intravenous grade magnesium sulfate taken orally with water (up to 24 mL/d of MgSO₄ 50% = 1166 mg/d of magnesium).¹⁴ Botulinum toxin has also shown success in the treatment of refractory erythromelalgia pain as evidenced by multiple case reports.^15,16 Aside from these reports, there is limited evidence to support the role of alternative therapies in the treatment of EM. Our aim is to demonstrate the efficacy of fish oil and a nutritional supplement containing bromelain, curcumin, and quercetin (BCQ™ by Vital Nutrients™) as key therapeutic ingredients in the treatment of primary EM.

Presenting Concerns and Clinical Findings

This case study examines an 81-year-old Caucasian female who presented to the National University of Natural Medicine (NUNM) Lair Hill Health Center for management of poorly-controlled primary EM. Her first reported episodes occurred in 2017, would occur at least monthly, last for 2-4 hours, and induce an intolerable amount of pain. Concomitant symptoms included vomiting and diarrhea during the episodes indicating the severity of pain and negative impact on quality of life related to this disorder. No skin changes during episodes, including erythema or swelling, were reported by the patient. The patient’s medical history included osteoarthritis, hypothyroidism, peptic ulcer disease (PUD) and depression. Due to her past history of PUD, she was unable to take the neurologist recommended daily dose of aspirin, and thus was seeking alternatives to the pharmaceuticals that had been recommended by her neurologist.

Diagnostic Assessment

The diagnosis of EM is based on clinical findings and a thorough history, as there is no single confirmatory diagnostic test.² Physical examination or photo documentation during an episode can support a suspected diagnosis of EM. Differentiating between primary and secondary EM is essential for appropriate management and can be made by screening for mutations in the SCN9A gene, which would suggest inherited primary EM. Additionally, laboratory workup, such as complete blood count with differential and liver function tests, should be completed to rule out an underlying myeloproliferative disease.^17-19 Some physicians will perform serologic testing for antinuclear antibody human immunodeficiency virus (HIV), and rheumatoid factor to rule out systemic lupus erythematosus (SLE), HIV and rheumatoid arthritis.¹ The role of skin biopsy in the diagnostic evaluation of this condition is controversial, although widely utilized, as the procedure lacks diagnostic specificity for both primary and secondary EM.^1,17,20 Electromyography, skin biopsy and nerve conduction velocity tests are considered to be valuable in the exclusion of neuropathies of different etiologies.^1,17,20

Prior to being seen at the NUNM clinic, the patient was diagnosed with EM by her neurologist. At that point she received diagnostic testing outlined in Table 1. She did not undergo skin biopsy or electrodiagnostic testing and a clinical diagnosis was made based on history alone. Her diagnosis was, again, confirmed clinically at NUNM based upon patient presentation and prior testing. No photo documentation of symptoms was available as the patient was unable to provide documentation and did not present to clinic during acute flares.

Table 1.

Timeline

Dates	Relevant Past Medical History, Diagnostic Testing and Interventions
Prior to 2017	Previous diagnosis of PUD
12/2017	Onset of sxs and initial dx. Pt reported sxs of EM in bilateral hands and feet and face. Pt utilized several topical medications including hydrocortisone cream, Benadryl, and Icy Hot. Pt reports application of ice pack to be most effective.
03/2018	ANA ELISA Screening: negative CBC with Differential: WNL TSH: WNL
05/2018	First visit with neurology. Pt reported total of six EM episodes since initial evaluation. Pt was prescribed aspirin 650 mg, gabapentin 600 mg, topical lidocaine 5% ointment, and advised to apply ice packs and take pain medication at onset of next episode. Also prescribed opioids for pain at this time.
10/2018	JAK2 Gene Screening: negative ESR: WNL Kappa Quant Free Light Chains: elevated Lambda Quant Free Light Chains: WNL Kappa/Lambda ratio: WNL Alpha 1 Globulin: WNL Alpha 2 Globulin: WNL Gamma Globulin: WNL ANA Screening: negative TSH: elevated Free T4: low

Abbreviations: PUD, peptic ulcer disease; sxs, symptoms; dx, diagnosis; EM, erythromelalgia; Pt, patient; ANA, anti-nuclear antibody; CBC, complete blood count; WNL, within normal limits; TSH, thyroid stimulating hormone; mg, milligrams; JAK2, Janus Kinase 2; ESR, erythrocyte sedimentation rate; T4, thyroxine.

Therapeutic Intervention

The patient was initially recommended topical lidocaine by an outside provider, which was unsuccessful in treating her EM flares. The subsequent therapies that were recommended and found to be insufficient in preventing episode frequency and severity may be found in Table 1. The patient reported heartburn with daily aspirin use at a dose of 325 mg and denied EM symptom improvement with additional dosing at onset of an episode. The patient also endorsed taking a nightly dose of gabapentin 300 mg and an additional dose at symptom onset, also without clear benefit.

Upon evaluation at the NUNM clinic, 2-4 grams of fish oil daily were recommended. The following month, the patient reported a decrease in symptom severity during the two episodes that had occurred since the previous visit. BCQ™ was added to her supplement protocol at a dose of six capsules daily. The patient returned the following month and denied episodes since the previous visit. She was advised to continue taking fish oil at the same dose and to increase BCQ™ by 3 capsules per day as the treatment was well tolerated and it was thought that the dose increase may further reduce inflammation to the benefit of the patient.

Follow-up and Outcomes

At follow-up one month later, the patient denied any EM flares since the previous visit. An increase in BCQ™ from six to nine capsules daily was advised at this time (Table 3.).

Table 3.

BCQ™ Supplement Facts

Serving size: 3 capsules

Boswellia serrata Gum Extract (alpha and beta boswellic acids min. 30% by HPLC)	600mg
Bromelain	300mg
Curcuma longa Rhizome Extract (total Curcuminoids min. 85-90% by HPLC)	600mg
Quercetin dihydrate (min. 90% by HPLC)	300mg

Abbreviations: Min., minimum; mg, milligrams; HPLC, high performance liquid chromatography

The patient was highly motivated and compliant with the daily supplementation regimen that was recommended to her at the NUNM clinic. At her most recent follow-up she remained symptom-free and also endorsed a noticeable improvement in mood, which is significant considering the psychological impact that EM episodes may have on patient quality of life.

Discussion

Aspirin is a mainstay pharmaceutical approach for the management of EM. Aspirin is an inhibitor of cyclooxygenase-1 (COX-1) and a modifier of cyclooxygenase-2 (COX-2), which binds irreversibly to its substrate.¹¹ It also irreversibly binds and blocks thromboxane A2 on platelets to prevent platelet aggregation.²¹ Anti-inflammatory lipoxins are produced as a result of COX-2 modification.^11,21 The primary mechanism by which aspirin exerts a therapeutic benefit in patients with EM is via anti-platelet activity due to COX-1 inhibition.¹¹ Recommended doses range from 325-650 mg per day, though a single dose of 500 mg has been shown to last up to three days.¹¹ Due to this long-acting effect, aspirin has been used diagnostically to evaluate EM secondary to myeloproliferative disease.¹¹ Aspirin has shown efficacy in cases of secondary EM with associated thrombocythemia, polycythemia and other blood dyscrasias, but has not been proven in the treatment of idiopathic EM, yet is still commonly recommended in the management of all EM subsets.¹⁸ Aspirin is contraindicated in those with a history of PUD, renal failure, hepatic insufficiency, or those with non-steroidal anti-inflammatory drugs (NSAIDs) hypersensitivity, which further indicates need for alternative therapeutic approaches.

Gabapentin and pregabalin have demonstrated variable efficacy in EM pain management. Some investigators suggest that mechanical allodynia associated with EM may be the result of a neuropathic pain mechanism and, as such, may be improved with administration of gabapentin by inhibiting release of glutamate, calcitonin gene-related peptide and substance P, all of which are involved in various pain mechanisms.^3,13 Systemic glucocorticoids have been reported to be beneficial in certain patients treated within weeks of symptom onset, suggesting that there is an inflammatory component to the pathogenesis of EM.²²

The combination supplement BCQ™ contains Boswellia serrata gum extract, Curcuma longa rhizome extract, bromelain and quercetin dihydrate (Table 3). This combination of antioxidants may reduce proinflammatory neurotransmitters substance P and glutamate, in turn reducing pain.³ Gum resins of Boswellia serrata, Indian Frankincense, contain boswellic acids (BAs), which, studies have shown, specifically inhibit 5-lipoxygenase (5-LOX) and exert an anti-inflammatory effect in the body.^23,24 The 5-LOX pathway forms leukotrienes (LTs) via arachidonic acid (AA) metabolism, which subsequently cause hyperalgesia and are implicated in the pathophysiology of neuropathic pain.^25,26 Curcumin has long been recognized for its anti-inflammatory and anti-oxidative properties and has also been investigated as a possible treatment for neuropathic pain due to its anti-nociceptive activity. In vitro studies have shown curcumin to be an effective scavenger of reactive oxygen species (ROS) and reactive nitrogen oxide species (RNOS), which is suggestive of its antioxidant properties.²⁷ Curcumin has also been shown to exert an anti-inflammatory effect via various molecular pathways, including inhibition of the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, both of which are implicated in various pain mechanisms. It is not well understood how inflammatory prostaglandins increase pain perception, but it is clear that COX-2 inhibition prevents arachidonic acid from converting to prostaglandins via the cyclooxygenase pathway.²⁸

As pertaining to the mechanisms mentioned above, we posit that BCQ™ exerts an anti-inflammatory, antioxidant, and analgesic effect on the vascular and inflammatory components of the pathogenesis of primary idiopathic erythromelalgia and should be considered as an adjunctive or alternative treatment option for this condition.

Fish oil supplements contain the omega-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Free PUFAs are thought to play a role in regulation of platelet activation when they are metabolized by the oxygenase enzymes cyclooxygenase, lipoxygenase and cytochrome proteins (CYP) into distinct classes of oxylipins.^29,30 It has been demonstrated that EPA and DHA inhibit platelet activation following enzymatic metabolism through all three of the previously mentioned pathways.²⁹ Because aspirin is a mainstay treatment for patients suffering from both primary and secondary EM, it is reasonable to assert that fish oil supplementation may act through a similar mechanism of action due to the role of PUFAs on inhibition of platelet activation. This treatment may be particularly effective and preferential for patients with a history of PUD or other contraindications to aspirin therapy.

The psychological, physical and social impacts of severe and persistent pain caused by EM often result in reduced quality of life and higher rates of morbidity and mortality compared with the general population.^3,4 This demonstrates the importance of novel therapeutic approaches in promoting remission and managing pain in patients with EM.

This patient’s symptoms are representative of primary idiopathic EM where pharmacologic management was both ineffective and contraindicated. In such cases, alternative therapies should be explored, as the pain and disability caused by this condition impacts quality of life to a significant degree.

The primary strength of this case is that daily supplementation with fish oil and BCQ™ was effective in ameliorating both the severity and frequency of EM episodes, while reducing the need for aspirin, thus providing PUD risk reduction and improving the patient’s quality of life. We postulate that the primary mechanism of action by which symptom mitigation was due to the anti-inflammatory and analgesic effects of both fish oil and BCQ™ supplementation and the anti-platelet action of the PUFAs from fish oil.

Limitations in this patient’s case were that the patient was lost to follow-up during the COVID-19 pandemic which limited patient care in 2020. Additionally, the pathophysiology of primary EM is poorly understood, thus targeted treatment options are limited. There is a paucity of research, specifically clinical trials, pertaining to EM treatments, as it is considered a rare condition. More research is needed to support efficacy and reproducibility of this treatment protocol.

Patient Perspective.

The patient was satisfied that the recommended treatment protocol improved both EM symptoms as well as mood. After the initial treatment response, following the first month of treatment, the patient expressed optimism at the decreased symptoms. The patient was encouraged that subsequent incidences of PUD may be reduced due to decreasing the need for aspirin by replacing this treatment with fish oil. She also noted a general decrease in anxiety, as the pain and duration of her EM had decreased and had become much more tolerable.

Table 2.

Timeline

Dates	Summaries from Initial and Follow-up Visits	Diagnostic Testing	Interventions
01/2020	First visit to NUNM Monthly episodes of EM attacks Sxs affecting bilateral hands and feet and face Associated sxs of nausea and diarrhea with all episodes	N/A	Treatment: 2-4 g fish oil qd
02/2020	Follow-up visit at NUNM Reported two episodes since first visit, occurring on 02/04/2020 Reported decreased severity of episodes Denied vomiting and diarrhea with recent episodes but endorsed abdominal cramping Swelling noted in hands and digits bilaterally Sensation intact in hands and feet bilaterally Rated overall improvement in symptom severity as 25-30%	N/A	Treatment: 2-4 g fish oil qd and BCQ™ 6 capsules qd Boswellia 1200 mg Bromelain 600 mg Quercetin 600 mg Curcumin 1200 mg
03/2020	Third office visit at NUNM Reported no episodes since previous visit	N/A	Treatment: 2-4 g fish oil qd and increase BCQ™ to 9 capsules qd Boswellia 1800 mg Bromelain 900 mg Curcumin 1800 mg Quercetin 900 mg
04/2020	Four-week follow-up phone intake Reported no new episodes	N/A	N/A
04/2020	Six-week follow up phone intake Reported that she was still sx-free Reported mood improvement	N/A	N/A
10/2020	N/A	MCV: mildly elevated TSH: WNL Free T4: WNL	N/A
11/2020	N/A	CMP: WNL except BUN at 25 mg/dL CCP: negative RF: negative ESR: 2 mm/hr	N/A

Abbreviations: NUNM, National University of Natural Medicine; EM, erythromelalgia; N/A, not applicable; g, grams; qd, once per day; sxs, signs and symptoms; dx, diagnosis; Pt, patient; CBC, complete blood count; MCV, mean corpuscular volume; TSH, thyroid stimulating hormone; WNL, within normal limits; T4, thyroxine; mg, milligrams; dL, deciliter; RF, rheumatoid factor; CMP, complete metabolic panel; BUN, blood urea nitrogen; CCP, cyclic citrullinated peptide; RF, rheumatoid factor; ESR, erythrocyte sedimentation rate; mm, millimeter; hr, hour