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12 Articles in Volume 17, Issue #2
Chronic Pain and Bipolar Disorders: A Bridge Between Depression and Schizophrenia Spectrum
Differences in Pain Management of Peripheral Vascular Disease and Peripheral Artery Disease
Duloxetine and Liver Function Tests
How Well Do You Know Your Patient?
Insurers End Policies Requiring Prior Authorization for Opioid Use Disorder
Letters to the Editor: Initiating Hormones
Managing Opioid Use Disorders and Chronic Pain
Opportunities and Challenges of Pain Management: The Family Physician’s Perspective
Pathways to Recovery From Co-Occurring Chronic Pain and Addiction
Strategies for Weaning Opioids in Patients With an Opioid Use Disorder and Chronic Pain
Treating Multiple Pain Syndromes: A Case Series Using a Functional Medicine Model
Treatment of Chronic Exhaustion and Chronic Fatigue Syndrome

Treating Multiple Pain Syndromes: A Case Series Using a Functional Medicine Model

Learn how applying a functional medicine model to manage the underlying causes of multiple systemic pain syndromes, using a more patient-centric team approach, helps improve care.

The current standard of medical care is a disease-based model. When patients present with uncomplicated acute pain, such as from a traumatic fracture, then a traditional medical approach is usually effective at providing relief. However, when symptoms persist beyond 3 months and become chronic, as with complex regional pain syndrome (CRPS) or fibromyalgia, then treatment will require a more patientcentric model of care, using multimodal therapies and interdisciplinary teamwork.

This is the basis for a functional medicine model that looks beyond the symptom-disease concept to identify and correct any mechanisms driving the disease process. These underlying issues may arise from imbalances and interactions between genes, diet, lifestyle, and environmental factors.1 When implementing evidence-based therapies that target pain mechanisms to resolve the disease-pain process, overall health and physical function are improved.

Two patients diagnosed with migraines, chronic fatigue syndrome, neuropathic pain, degenerative arthritis, and fibromyalgia, following failed trials of the prescribed analgesics: duloxetine and pregabalin, were assessed and treated using the functional medicine model. Their cases are presented here.

Patient Case 1

Patient A, a 43-year-old married mother of 2 teenage boys, presented with a chief complaint of chronic widespread pain that had worsened over the past 15 years. Her pain symptoms included daily headaches (with the pain radiating from the occipital region on the left side to the frontal area), joint pain and stiffness, irregular periods, and chronic sinus congestion.

Medical History

This patient had been diagnosed previously for common migraines, depression, anxiety, chronic rhinitis, asthma, mild eczema, and benign positional vertigo. She reported experiencing headaches nearly every day, which worsened in the presence of strong odors, such as perfumes, auto exhaust, and dampness, and that these headaches had begun in childhood. She also was experiencing joint pain in the shoulders, knees, hands, and fingers with an overall average numerical pain rating score of 6 out of 10 on a near-daily basis. She reported experiencing allergies when exposed to mold, dust, and nickel. Also, she was troubled by low energy and brain fog.

Three years ago, she had a mammogram, physical exam, and Pap smear, all of which were normal. She reported having had no surgeries, motor vehicle accidents, or known concussions. The patient had no symptoms to suggest seronegative, autoimmune, or demyelinating diseases.

Her family history was positive for atopy, Asperger’s syndrome (both sons), type 2 diabetes, obesity, migraines (both parents), brain cancer (grandparent), and breast cancer (aunt). She was a former smoker who quit 17 years ago and did not drink alcohol or use recreational drugs. She averaged 3 to 4 cups of coffee every morning. In her leisure time, she enjoyed playing guitar, hiking, and photography.

Patient A reported using a variety of prescription medications, including nonsteroidal anti-inflammatory drugs, triptans, topiramate, gabapentin, and paroxetine (20 mg/day), and was taking a micronutrient supplement of vitamins D, B complex, and a multivitamin. In addition, she had sought pain relief from chiropractic care, physiotherapy, and acupuncture and had accommodations for workplace ergonomic corrections. She had had a thorough workup with negative results from a variety of specialists, including an endocrinologist, a neurologist, and an otolaryngologist.

Diagnosis and Treatment

Physical findings for patient A were unremarkable (Table 1) and test results for sleep apnea were normal. She was diagnosed with cervicogenic headaches with migraine features. Then she was referred to a naturopathic doctor who recommended dietary changes, including avoidance of aspartame and sugar-containing foods, as well as dairy products, to reduce possible triggers to her migraines exacerbations. She also was referred to an environmental medicine consultant for a more advanced exploration of her response to allergens.

Environmental Consultation

The patient was seen in March 2015 by an environmental medicine specialist to review potential exposures, causal links, and genetic polymorphisms (Tables 2 and 3). During the evaluation, she reported that symptoms, including the headaches and joint pain, started during a home renovation that exposed mold that had developed following recent water damage.

Given her symptoms of multiple environmental chemical sensitivities syndrome, the patient was directed to complete an environmental questionnaire and lifestyle genomics profile and to undergo standard lab tests, including a urine oxidative damage panel.

An assessment of her unique genomic profile revealed several genetic polymorphisms associated with impairments in detoxification and methylation; more specifically, she had GSTM1 and GSTT1 deletions, which made her more susceptible to exogenous toxins.1 These deletions challenged her ability to upregulate glutathione induction in response to exposure.2,3

She also was homozygous for an at-risk allele for SOD2, which impaired biosynthesis of superoxide dismutase, a potent endogenous antioxidant required for mitochondrial cellular protection.4 The methylation profile also revealed several at-risk alleles related to absorption, assimilation, transport, and metabolism of cobalamin and folate, which may compromise the functional capacity of the methylation cycle, leading to disturbances in cellular repair, stress response, and bioenergetics.5

When Patient A returned to the functional medicine clinic in April 2015, she mentioned that she was attempting to taper off the paroxetine. She also reported a flare in joint pain, but no effusions were noted. Her genetic profile and biotransformation imbalances were reviewed with her in detail. She was told that the inflammatory markers test and the oxidative stress profile came back normal. However, she had a markedly elevated complement protein, C4a, suggesting mycotoxicity to mold. Also, she had a high normal mean corpuscular volume of 97, which was suggestive of hypomethylation.

Follow-Up Treatment

Patient A was started on oral glutathione. She returned to the clinic in June 2015 with complaints of worsening joint pain and an inability to stop the paroxetine. She also reported not having had her menstrual cycle since October 2014, and she requested help with worsening depression.  

To address the patient’s depression, a course of 4 weekly treatments of a micronutrient cocktail (Myer’s protocol with glutathione) was administered intravenously,6 and she received an oral supplement containing St. John’s wort (SJW), passiflora, and valerian to augment serotonin biosynthesis, release, and postsynaptic receptor sensitivity. The dose of SJW was low enough to avoid interaction with the antidepressant medication she was taking, and the oral supplement has been used in Europe to wean patients off prescription antidepressants.7 For the headaches, she was given a butterbur and quercetin formula as a biological response modifier for vasomotor instability,8 as well as a bioactive B vitamin supplement and a botanical formula containing agnus castus and cimicifuga to normalize endocrine function.

The patient returned to the clinic 1 month later (July 2015) with persistent headaches and joint pain. She reported that her depression was nearly resolved. She was started on an oral anti-inflammatory nutraceutical containing white willow, natural eggshell membrane, boswellia, ginger, and turmeric that mechanistically acted to modulate leukotrienes, cyclo-oxygenases, prostaglandins, chondrocytes, and pro-inflammatory cytokines such as interleukin 6.9-11

She was advised to continue the antidepression supplement and the active B formula, but the infusion therapy was temporarily discontinued and she was referred to a certified building biologist to more actively manage her exposure to residential mold.

When seen in November 2015, Patient A reported her joint pain was reduced by 60% based on a Systems Questionnaire and her anxiety was reduced, but the chronic headaches persisted. She was started on orthomolecular doses of nicotinic acid to down-regulate prostaglandin release from mast cells, a possible mechanism of chronic headaches.12 Additional blood tests and a thermal scan were ordered to assess evidence of hypo/hyperperfusion.

One week later, she returned to the clinic complaining of intensifying headaches and sinus congestion. In response, she was started on aggressive mold treatment, including oral and nebulized glutathione, to upregulate innate immunity and phase II conjugation,13 as well as a botanical formula containing grapefruit extract, burdock root, berberine alkaloids, and olive leaf extract and a topical lymph drainage formula.14 Also, she was urged to initiate a stronger antimold protocol.

In early December 2015, she was prescribed an intranasal amphotericin B spray at a concentration of 0.25% to be used every morning and a 1% disodium E ethylenediaminetetraacetic acid nasal spray to be used at bedtime in addition to cholestyramine, a sequestering agent to bind the mycotoxins (3 times a day), to address the headaches and congestion.

When the patient returned to the clinic in February 2016, she reported a significant reduction in intensity and frequency of headaches for the first time in years. She was advised to continue with the anti-inflammatory and mood-enhancing supplements, L-glutathione to compensate for the genetic deletions of GSTT1 and GSTM1, and the antimold nasal sprays.

After a month on this protocol, she reported that her joint pain had fully resolved, her energy was 80% improved based on a Fatigue Severity Scale, and her headaches had reduced in both frequency and intensity by 75% as determined with a Headache Screening Questionnaire. Since results of blood testing revealed that the patient had a low morning cortisol level, an adrenal fatigue repletion formula15,16 was prescribed; the patient received a standardized organic herbal extract containing licorice root, glycyrrhizic acid, holy basil leaf oil, eleuthero root, eleutherosides, rhodiola root, salidroside, hawthorn leaf and flower, vitexin, and alfalfa. In particular, the formula containing licorice was prescribed to improve cortisol levels and reduce fatigue.

When Patient A was seen in May 2016, she noted improvement in all areas, including pain, congestion, headaches, and energy. She presented with a new diagnosis: kidney stones, of undetermined origin. With follow-up lab testing, the patient showed a reduction in carbonic anhydrase, C4a, that went from 9960 to 3351, suggesting less complement activation from the mold toxins. In response, she was advised to taper off the antimold nasal spray.

In September 2016, the patient reported that her headache frequency and intensity remained improved and the widespread pains and fatigue complaints were essentially resolved.

Assessment and Discussion

Patient A’s joint pain, stiffness, chronic congestion, mood, and energy were all biological consequences, or endpoints, of a genetic predisposition to impaired detoxification and methylation in which she was a poor responder to environment mold exposure.

While other patients who have a different genetic pattern and ancestry may have similar exposure to mold, their detoxification capacity might be better suited to clear the exposures with no resulting illness. Homocysteine levels above 7 and a mean corpuscular volume above 90 are suggestive of hypomethylation; the C4a test is a biomarker of complement activation in response to mycotoxins that can be used to screen and follow patients. Further testing, including SPECT imaging to detect perfusion deficits that may occur in CFS and postconcussion patients, and to evaluate for specific mycotoxins such as aflatoxin, ochratoxin A, and trichothecenes are available at specialized lab testing centers.

Mold toxicity is a known underlying root cause for some patients with non-remitting headaches, fatigue, and widespread pain. In summary, 3 key hallmarks of mycotoxicity in recalcitrant fibromyalgia patients are:  

  • Persistent headaches that are non-responsive to traditional migraine medications 
  • Chronic sinus congestion
  • Multiple environmental sensitivities

When mold is suspected, or there is known exposure to water damage in the home or office, clinicians should consider ordering an environmental workup. The next step would be confirmatory lab testing (HLA-DRBQ) for susceptibility, presence of the C4a marker, and urinary mycotoxin levels.

Patient Case 2

On October 10, 2012, Patient B, a 45-year-old financial advisor and mother of 2 boys, presented with chronic headaches and neck and low back pain with bilateral sciatica. The patient described suffering from widespread, migratory muscle pain, which had been present since the patient was 18 years old. The onset of pain was sudden and precipitated by acute lymphadenopathy of unknown origin, which resulted in right neck lymph node dissection and complicated by thoracic nerve palsy. She also recalled a possible “bulls-eye rash” without acknowledgment of a tick bite. Symptoms were aggravated by a possible autoimmune reaction (left-sided neck-arm pain) after giving birth to her first son 9 years ago.

Health and Family Medical History

Patient B reported symptoms of chronic constipation (2 bowel movements/week), shortness of breath on exertion, random twitching, tingling, cognitive difficulties (impaired memory), heartburn, fatigue described as 5 out of 10 on a numerical scale, and difficulty sleeping. She reported an allergy to sulfa drugs and a normal report from her last gynecological exam.

She was taking the following medications: oral contraceptive, ibuprofen, acetaminophen/methocarbamol (Robaxacet), acetaminophen, and a topical corticosteroid for rosacea. In addition, the patient was taking naturopathic therapies that included a progestogenic botanical formula;17 a spasmolytic; a GABA agonist supplement containing magnesium citrate, calcium lactate, valerian root, passionflower, lemon balm, and hops;18-20 and a kinase modulator known as Kaprex21 to modulate genetic transcription and inflammation and downregulate the transcription factor NF-kB, which is involved in regulating immune function. This patient reported family members with asthma, hypertension, COPD (father), and diabetes (mother and grandfather).

By February 2013, she self-reported a 30% improvement overall but noted that she was experiencing flu-like symptoms and that it “feels like I am fighting an infection all the time.” She had sought out massage therapy and chiropractic care, which only provided temporary relief.

When reviewing her lifestyle habits, the patient stated the following: she was currently a nonsmoker but had smoked during her teen years and was exposed to secondhand cigarette smoke as a child; she averaged 2 cups of coffee daily and wine once weekly; she did not use or try any recreational drugs; she followed a typical American diet but had a tendency to skip meals; and she reported a high level of stress, trying to balance work and family responsibilities.

Patient B’s physical findings were suggestive of bilateral ulnar neuoropathies, but ultrasound and EMG testing were negative. She did have positive results for Roo’s, Adson’s, and Halstead’s tests for vasculogenic thoracic outlet syndrome, which was later confirmed on the left with Doppler ultrasound.

Preliminary Diagnoses

Patient B was diagnosed with myofascial pain and fibromyalgia (fulfilling the American College of Rheumatology criteria with Widespread Pain Index [9/19] and Symptom Severity Scale [5/12]) and left-sided thoracic outlet syndrome due to tight scalene muscles. Her DN4 pain questionnaire score was 6 out of 10, which met the criteria for diagnosing neuropathic pain. Laboratory tests were ordered (Table 4).

In addition, the patient was diagnosed with the following: progesterone insufficiency; hypercortisolemia, cobalamin (B12) insufficiency that was likely producing hypomethylation; vitamin D insufficiency; small intestinal bacterial overgrowth (dysbiosis); dysfunctional uterine bleeding, for which she was advised to discontinue the oral contraceptive; and a possible diagnosis of chronic Lyme disease based on a low CD57 lymphocyte count.

Treatment and Follow-Up

The patient was started on an hypothalamic–pituitary–adrenal axis-regulating supplement that contained rhodiola, taurine, and glycine23 to help alleviate recent marital and financial stressors; an endocrine-modulating formula called Pascofemin for uterine bleeding; and a choleretic/hepatic mixture called Quassia for bowel regularity and bile flow.21,22

When assessed on June 13, 2013, Patient B reported that her uterine bleeding had ceased and her bowel movements had increased in frequency to every other day (from every 4th day). As the ELISA Public Health test for Lyme disease was negative, additional testing (IGeneX) was ordered.23 Following the Centers for Disease Control and Prevention criteria, the second test confirmed Lyme disease based on 5 positive IGM bands on the Western blot.24 Patient B was referred to an infectious disease specialist who initiated treatment for chronic Lyme disease, which included doxycycline, azithromycin, hydroxychloroquine, nystatin, and metronidazole (taken in 2-week cycles).

The patient was instructed to follow a diet that removed all gluten, sugar, and yeast-containing foods. When she returned to the clinic in October 2013, her symptoms had worsened due to a Herxheimer reaction to the antibiotics. In response, all antibiotics were discontinued for 7 days, followed by a reduced dose of doxycycline, azithromycin, and metronidazole cycled over 3 consecutive days a week.

Based on lab results, the patient began cobalamin intramuscular injections monthly. She also was prescribed a bioactive B vitamin, chelated magnesium, a probiotic of Saccharomyces boulardii—a fungal competitive antagonist to prevent yeast overgrowth from the antibiotics, a neuroprotective formula that contained alpha-lipoic acid, a coenzyme Q10 supplement, N-acetylcysteine, acetyl-l-carnitine, phosphatidylserine, sulforaphane glucosinolate (SGS),25-31 an immunomodulatory formula with ganoderma to modulate T-lymphocyte activity,28,29 and silymarin as a hepatoprotective.32

Patient B returned to the functional medicine clinic in December 2013, at which time she reported dizzy spells, loose stools, and fatigue, but her chronic widespread pain had almost completely resolved, and she was sleeping better. The patient was instructed to continue the immunomodulatory botanical formula. In addition, a D-ribose formula was added to upregulate bioenergetics through activation of the pentose phosphate pathway.33,34 A homotoxicology formula called Pasconal, containing avena and valerian, was added to improve her sleep and reduce the neuropathic pain.35

In February 2014, the infectious disease specialist altered her antibiotic regimen, increasing the doxycycline, azithromycin, hydroxychloroquine, and metronidazole and adding vitamin B6, to be taken in 2-week cycles. Within a week, the dizzy spells had resolved, and her cognitive function was restored. She also reported an improvement in her arm and shoulder pain, responding to the exercises she was taught for the thoracic outlet syndrome. She mentioned a concern about experiencingunintentional weight loss. Upon inquiry, she admitted to following a very regimented diet. The patient was advised to increase the variety of her food selections and to add coconut oil liberally to increase medium-chain triglyceride intake.36,37

In April 2014, her bowel movements were normalized. Follow-up testing for bioimpedance and body composition revealed improved body composition and weight gain. The patient presented with a new complaint of postnasal drip and other allergic symptoms, for which she was prescribed a plant sterol to desensitize and downregulate humoral immunity and IgE biosynthesis.

By early May, the patient was feeling well enough to taper the antibiotics, and she was instructed to stop the hydroxychloroquine, nystatin, and metronidazole. This led to a reoccurrence of pain and fatigue. She was then prescribed a pulsatile protocol of antibiotics: clindamycin, quinine sulfate, nystatin, clarithromycin, and metronidazole. She fell in the healthy weight range, and all vitals were normal.

When Patient B returned to the clinic in early June 2014, she was advised to continue taking the silymarin formula, plant sterol, vitamin C, Pasconal, and a phytoadaptogenic supplement that contained glycyrrhizin and eleutherococcus.38,39 She was also instructed to continue coenzyme Q10 and the immunomodulatory formula. All other supplements were discontinued. The patient was referred to a bioidentical hormone–trained physician for individualized therapy, and following that she was started on micronized oral progesterone.

As Some Symptoms Go Away, Others Arise

At the beginning of September 2014, she reported significant improvement in her anxiety and sleep, which was attributed to the micronized progesterone. The pain was well controlled, so she requested that we address her poor memory and concentration. In response, she was started on a nootropic formula, containing vinpocetine and ginkgo to optimize neurovascular flow; huperzine A, an inhibitor of acetylcholinesterase; and phosphatidylcholine.40,41 This formula was provided to increase neural production of acetylcholine, as well as bacopa, a free radical scavenger and antitoxin, to enhance cell-to-cell communication. Also, her infectious disease specialist added a low-dose naltrexone to her program.

In mid-January 2015, Patient B presented with high serum estrone levels and was diagnosed with estrogen dominance. She was started on an estrogen-clearing formula, which included trimethylglycine and pyridoxine to enhance methylation, and chrysin and isoflavones as selective estrogen response modulators.42      

By the end of March 2015, her antibiotics were discontinued and she was feeling well. However, she started to experience symptoms of gastroesophageal reflux disease and her constipation returned. The patient was started on a botanical formula to optimize digestive function that included gentian to settle her stomach, peppermint to reduce flatulence, lemon balm an anti-spasmolytic, and rhubarb to normalize transit time. The patient was prescribed a balanced micronutrient cocktail to replete cellular deficiencies and modulate her stress response. The therapy was infused twice monthly until September and then changed to an immunity formula, which was continued monthly for a full year.

On follow-up in June 2016, Patient B reported feeling very well with abundant energy and improved memory and concentration, as well as improved vision. The bowel frequency was improved but still not optimal. In July, her health was maintained without antibiotics, and she reported an energy level on a numeric scale of 7 out of 10. By September 2016, her bowel regularity had normalized by the herbal preparation containing rhubarb to increase peristalsis.

Although this patient was diagnosed with several conditions, the long-term underlying chronic Lyme disease infection had initiated a cascade of hormonal, neural, intestinal, inflammatory, and immunological changes that crossed multiple systems—and typically would be treated by different specialists in isolation. The biological response to multisystemic infectious disease syndrome, which included Lyme disease and its coinfections, was debilitating. Through perseverance and determination, the patient was able to gradually recover her full health, improve functionality, and restore her quality of life with full resolution of her chronic widespread neuropathic pain.

Functional Medicine for Pain Relief

Both patients had clinically significant pain reduction and improved function as documented with both subjective and objective outcome measures up to 36 months after treatment initiation. No serious adverse events arose over the course of treatment, suggesting that both women responded well and all treatments were well tolerated.

This novel case series proposes that a functional medicine model may be of benefit in the management of patients with chronic pain and fatigue conditions. Further investigations with larger, homogenous patient populations done in blinded, randomized, controlled trials are warranted.

In each of the case studies, instead of relying solely on the conventional diagnosis of fibromyalgia, the patients received individualized functional medicine diagnoses with appropriate follow-up and treatments. In each case, the patient showed a positive response to her extended, personalized, multifactorial treatment. Subjective outcome measures included the short-form McGill Pain Questionnaire, DN4 questionnaire, Medical Symptoms questionnaire, and Fibromyalgia Impact Questionnaire—all of which showed improvement from the time of diagnosis to the end of treatment.

Patient Case Discussion

It is important, especially in cases with complex pain syndromes, to thoroughly evaluate the patient and search for clues and connections to as-yet-undetected underlying causes of the pain response. The multifaceted treatment decision-making process involves a myriad of products that may be tried in managing individual responses to treat pain and comorbid symptoms, a process that is provided by the functional medicine model.

The functional medicine model is a personalized systems biology approach that uses emerging research to address the fundamental mechanisms producing the symptoms. Although many patients are given the same disease name, their stories are different, and the underlying dysfunctions and processes are unique to each patient.

The functional medicine approach seeks to understand how impairment in a system upstream (cause) leads to a pathology downstream, namely the disease or symptom (effect). For example, many research studies offer theories for the causes of chronic fatigue syndrome and fibromyalgia.43-50 Factors such as toxin-induced oxidative stress and mitochondrial damage,43,44 altered microbiome and microbe-induced microglial activation,43 viral infections,44 and the effects of Lyme disease,47 among others, have all been proposed as the cause of central sensitization, pain amplification, and fatigue in this patient population. A functional medical model applies these emerging concepts into a personalized medical approach for each patient and seeks to identify the unique root causes specific to the individual.

With the advent of the “omics” revolution in the 21st century, it is timely to redirect medical care to a more personalized medical approach. By using a systems-oriented approach and engaging both patient and practitioner in a therapeutic partnership, functional medicine seeks to restore the patient’s overall health. Functional medicine aims to address the whole person such that practitioners spend extended time with the patient, listening to the person’s health history and then looking at the interactions among genetic, environmental, and lifestyle factors. The gene-environment intersection is a root cause of health and disease, and epigenetic solutions can be applied for long-term, sustainable health, and disease resolution.51 In essence, the functional medicine model necessitates an evolution in the practice of medicine that better addresses the healthcare needs of our chronic pain patients.

This case series highlights the importance of patients’ willingness to respond to changes in supplementation, making the functional medicine model a good example of an individualized, patient care approach. While evidence-based medicine is critical in informing the treatment choices for isolated therapeutic agents, this approach constrains practitioners from employing a patient-cenric approach.

To implement a functional medicine approach to care effectively, taking a detailed history that incorporates genetic and environmental factors is essential. Both the Canadian and US healthcare systems reward physicians for seeing more patients with 1 diagnosis or chief complaint, rather than offering every patient a comprehensive, thorough patient-centric approach, as currently practiced by functional medicine specialists.52

Future clinical research is needed to include larger studies with specific patient cohorts and comparative socioeconomic costs, in order to further validate such a model aimed to improve quality of life for our chronic pain patients.

Last updated on: June 21, 2017
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Treatment of Chronic Exhaustion and Chronic Fatigue Syndrome

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