Autoimmune Conditions and Chronic Pain

• Chronic pain is associated with autoimmune conditions.
• Tricia Heitman, PharmD, presented this on March 27, 2025, as part of a Personalized Medicine Certification.

Autoimmune Conditions & Inflammatory Pain

• Rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) belong to autoimmune conditions associated with inflammatory pain.
• Other autoimmune conditions associated with inflammatory pain include psoriatic arthritis, ankylosing spondylitis, myositis (including dermatomyositis), Sjogren's syndrome, and multiple sclerosis (MS).

Autoimmune Conditions & Neuropathic Pain

• Autoimmune conditions associated with neuropathic pain include Sjogren's syndrome, psoriasis/psoriatic arthritis, and Guillain-Barre syndrome.
• Type 1 diabetes, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA) are also autoimmune conditions associated with neuropathic pain.

Immune System & Pain

• Pain results from inflammation that can trigger antibody-mediated complement activation or the release of proinflammatory cytokines or peptides.
• B-cell dysregulation in autoimmune disease enhances auto-antibody production, leading to pain.
• Molecular mimicry leads to direct IgG-induced injury of nociceptive fibers, causing pain.

Pro-nociceptive Antibodies

• Anti-citrullinated protein antibodies can produce mechanical and thermal hypersensitivity in mice when administered intravenously.
• Immune complexes with collagen type II antibodies cause calcium release in approximately 40% of TRPV1 capsaicin-sensitive cells.

Toll-Like Receptors (TLRs)

• TLRs are positioned at the neuroimmune interface.
• Inflammatory consequences of TLR activation on glia, sensory neurons, and other cell types can influence nociceptive processing and lead to exaggerated and unresolved pain.

Pain

• Pain is an unpleasant sensory and emotional experience linked to actual or potential tissue damage.

Forward-Thinking Pain Relief Options

• Forward Thinking Pain Relief Options include oxytocin (OT), ketamine, low-dose naltrexone (LDN), and magnesium.
• Other Forward Thinking Pain Relief Options include methylene blue, vitamin D3 and low-dose GLP-1s

Oxytocin & Chronic Pain - Mechanism

• Oxytocin directly agonizes the TRPV1 channels.
• TRPV1 channels are heat and capsaicin receptors.
• TRPV1 channels are located in the afferent somatosensory neurons and along the spinal cord.
• Activation of TRPV1 with capsaicin provokes stronger responses to oxytocin.

TRPV1 Agonists/Antagonists

• They are strong candidates for new drug development.
• One of the most studied mechanisms for treating inflammatory pain involves TRPV1.
• A problem: Most agonists alter core body temperature, and capsaicin causes pain before desensitization.

TRPV1's Role in Chronic Pain

• TRPV1 receptor alteration in response to inflammation is crucial for the transition from acute to chronic pain.
• Upregulation of TRPV1 amplifies pain signals.
• Upregulation occurs in the presence of inflammation.

Oxytocin & Autoimmune Disease

• Oxytocin suppresses the up-regulation of toll-like receptor 4 (TLR4).
• Oxytocin suppresses the release of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha).
• Oxytocin inhibits the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway.
• Oxytocin modulates neutrophils, mast cells, and macrophages.

Immune Function / Depression

• Oxytocin alleviates emotional disorders by modulating the hypothalamic-pituitary-adrenal (HPA) axis and the central immune system.
• Dysfunction of the immune system is strongly linked to the onset and progression of depression.
• Oxytocin can be an adjunct to antidepressant treatment, alleviating depression symptoms by decreasing responsiveness to stressful behaviors.

Oxytocin: The Big Picture

• Oxytocin via the TRPV1 pathway alters the perception of pain associated with peripheral inflammation.
• Oxytocin can help reduce the response to stress and reduce markers of inflammation.

Arthritis

• Oxytocin levels are reduced in patients with osteoarthritis.
• Oxytocin has a stimulatory effect on bone development.
• Oxytocin mediates endogenous analgesia in animal and human studies, providing support for its possible interest in osteoarthritis and its potential therapeutic treatment.

Migraine Headache Prophylaxis

• Inflammation dramatically upregulates the number of oxytocin receptors available on trigeminal neurons.
• A follow-on open-label study found that one month of intranasal oxytocin dosing showed a reduction in pain and a more impressive decrease in the frequency of headaches in chronic and high-frequency episodic migraineurs.

Post-Surgical

• Pre-incisional subcutaneous oxytocin administration reduced the hemodynamic response and diminished postoperative pain.

Chronic Pelvic Pain in Women

• A 2-week course of oxytocin administration improved pain severity compared to placebo, without affecting pain-related interference.

Back Pain

• Oxytocin reduces pain sensitivity in patients with back pain.
• Oxytocin utilization can lower the dose or need for medications with a higher side effect profile.

Anxiety Disorders

• Low-dose frequency chronic intranasal oxytocin has the potential to alleviate exaggerated neural threat reactivity in subjects with elevated anxiety levels, suggesting a treatment potential.

NSAID Use with Oxytocin

• Patients taking NSAIDs such as ibuprofen within 24 hours before receiving intranasal oxytocin experienced significantly less relief than patients not taking NSAIDs.
• Yeomans et al. theorize the expression of oxytocin receptors is driven by inflammatory cytokines, and the anti-inflammatory properties of NSAIDs block the oxytocin receptors in the trigeminal system.

Ketamine (Racemic)

• Ketamine is Nonbarbiturate dissociative anesthetic Noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist and Glutamate receptor antagonist

Ketamine Mechanism of Action

• Ketamine's effects in depression and chronic pain outlast the actual drug levels, likely due to increased structural connectivity from increased glutamine release from synapses.

Nasal Ketamine (Racemic)

• Sub-anesthetic doses are used for pain.
• Bioavailability is approximately 50%.

Ketamine Nasal Spray Utilization

• Acute pain management with ketamine nasal spray may reduce the need for opioid use.
• Ketamine nasal spray is safer than opioids in patients with hemodynamic instability or potential respiratory and airway compromise.
• Nasal spray is simpler and faster to administer.
• Analgesic effects begin within 10 minutes and may last up to 60 minutes.
• Ketamine nasal spray for chronic pain is typically dosed 3-4 times per day.
• Combining ketamine with morphine treatment reduced the windup phenomenon (central sensitization).

Notable Side Effects of Ketamine Nasal Spray

• Dizziness (21.7%), nausea (17.0%), difficulty concentrating (58.3%), confusion (50.0%), emergence phenomenon (30.0%), and dry mouth (25.0%).

Sublingual Ketamine (Racemic)

• Sub-anesthetic doses are used for pain.
• Bioavailability is approximately 30%.

Sublingual Ketamine - Dosage Discovery

• Starting dosage suggestion: 25 mg TID, titrated to achieve desired results.

Sublingual Utilization

• Used for long-term chronic neuropathic pain with Fibromyalgia, trigeminal neuralgia, spina bifida, and diabetic neuropathy.
• Use reduces opioid, gabapentin, and benzodiazepine use by 59%
• It's known to have Good long-term safety profile

Oral Ketamine

• Sub-anesthetic doses are used for pain.
• Used for chronic pain management
• Bioavailability is approximately 20-25%.
• It's used for Complex, chronic neuropathic pain also Chemotherapy and Central sensitization

Oral Ketamine Utilization

• Pain was reduced in 2/3rds of patients with chronic neuropathic pain and chemotherapy-induced neuropathy
• Patients with cardiovascular disease or high blood pressure should be monitored.

Oral Ketamine – Dosage Discovery

• The starting dose is then Up-titrated in 25 mg increments or 20-50% of the starting dosage
• Up-titration occurs every 3 days until pain relief is achieved the day after dosing, side effects prevent further up-titration, or the ceiling dose failed to provide an appropriate response.

Oral Ketamine Study

• Open-label trial with 32 adults aged 22-72 years. Also 53% were female which Lasted for 6 weeks
• Dosage: Once weekly dosing – 0.5 mg/kg titrated to a max of 3 mg/kg
• Titration: up by 0.2-0.5 mg/kg or down by 0.2-0.7 mg/kg at each weekly treatment
• Patients would be supervised for 90 min following each dosage

Oral Ketamine Study exclusion criteria

• History of psychosis and/or mania/hypomania
• Acute suicidality requiring urgent psychiatric intervention
• Uncontrolled/severe symptomatic cardiovascular disease
• History of intracranial mass, intracranial hemorrhage/stroke, cerebral trauma/traumatic brain injury, or increased intracranial pressure
• Liver function test results out of normal range
• Previous reaction to ketamine
• Pregnancy or breastfeeding

Oral Ketamine Study result

• The treatment was generally well tolerated with No participants withdrew from the trial
• Most frequent side effects: Decreased energy and fatigue, Anxiety, Poor concentration, Restlessness, General malaise, Dry mouth, Dizziness and tremors

Ketamine Use in Refractory Anxiety

• Anxiety: Approximately 25% of the population meet the criteria for anxiety diagnoses with Incident rates are continuing to increase
• Current Standard of Treatment which includes First line, SSRI, SNRI, Psychotherapy (cognitive behavioral therapy) and Second line High potency benzodiazepines
• Is Considered refractory when administration of standard treatment is either ineffective or minimally effective.

Anxiety and Neural Plasticity the Role of Ketamine

• Anxiety patients are suffering from Refractory anxiety and Impaired threat /safety discrimination.
• They also impaired Myelin plasticity in response to external conditions and Decreased white matter tract connecting the brain regions regulating a response to threat with regions responsible for regulating behavior
• Ketamine can help with Transient normalization of structural plasticity in the brain

Ketamine Use in Refractory Anxiety – Treatment Eligibility Considerations

• Ketamine allergy, Heart health, Untreated high blood pressure, Unstable thyroid disease, Elevated intraocular pressure, Elevated intracranial pressure and Urological health
• These should be factored into the treatment eligibility also Trauma history, Suicide history, Ongoing alcohol or substance abuse which also includes Opioid use disorder and Active psychotic or manic disorder
• Use Sublingual study approach as a Telehealth approache with a Dosage 5 mg/kg as ketamine dissolvable tablets
• Saliva would be held in the mouth for 7 minutes then saliva was spit out rather than swallowed while Patients were to stay in the supine position with an eye mask and headphones for an hour then journal followed by a meeting with a professional therapist
• 79.3% of patients achieved improvement along with a Clinical outcome that includes Ongoing sessions seem to enhance benefit

Side Effects

• (reported by 4.7% of patients) Included Elevated heart rate, Worsening anxiety and depression, Increased urinary pressure and hematuria

Review Results

• Sublingual and IV injection should Dosage range to 0.25-1 mg/kg for Treatment response occurred within 3 hours and lasted up to 14 days after injection
• Oral dosage that includes anxiety associated with palliative care should equal Oral dosage 0.5 mg/kg with an Anxiety reduction at 60 min with 50-85% drop in anxiety scores for Oral dosage and
• Modified release ketamine capsules should increase 60-240 mg based on tolerability Given every 12 hours to be Able to achieve a fear reduction of 50% whereas Only one of 7 patients experienced disassociation

LDN Mechanism in Pain

• LDN Hormesis exhibits a Biphasic dose response meaning it can be an Inhibitor at high doses or an Agonist in low doses
• Reduces glial activation, Upregulates endogenous opioid signalling, Blocks endogenous opioid signalling and Releases of pro-inflammatory cytokines
• Analgesic effects: "blockage of mu- and delta-opioid receptors and to a lesser extent kappa-opioid receptors in the central nervous system leading to a feedback-mediated increase of these receptors and improving the endorphin system" whilst Suppresses substance P (TAC1)
• Anti-inflammatory effects blockage of the toll like receptor 4 (TLR-4) in the microglia cells, at central nervous system”

LDN Opioid Receptor Effects

• LDN may reduce pain and act agonistically by triggering positive feedback mechanisms
• LDN causes a transient opioid receptor blockade that then prompts the body to compensate for reduced receptor activity by upregulating both endogenous opioids and opioid receptors. For example, LDN stimulates the production of the body's endorphins, which represent natural opioids."
• LDN may also have immuno-modulatory effects by stimulating the production of enkephalin (derived from its precursor proenkaphilin, PENK)
• This acts a messenger that commands the immune system to decrease the production of an inflammatory agent called Substance P (Tachykinin Precursor 1, TAC1)”

Naltrexone Pharmacokinetics

• After oral administration the half-life is 4 hours and Naltrexone's major active metabolite, 6β-naltrexol, persists for approximately 13 hours
• It also has a weaker affinity to the opioid receptor and Naltrexone is primarily excreted by glomerular filtration

Low Dose Naltrexone

• Selling Points for Pain are that it’s Affordable, Analgesic and anti-inflammatory and has Few side effects but the Negatives are that the treatment isn’t well known for pain , Cannot be used with opiates and that More studies are needed in the area

LDN Dosage

• Naltrexone is considered a low dose between 1-6 mg per day.
• Opioids can induce a massive release of inflammatory cytokines and disruption of intestinal barrier function by activating toll-like receptors 2/4 (TLR2/4), eventually resulting to sustained bacterial transmission and persistent systemic inflammation.
• With Arthritis Pain : reduction in the use of NSAID, opioids, and DMARDs

Fibromyalgia

• “Overall, LDN was found to be effective in the symptomatic management of FM, and of the 78% of included studies that evaluated for safety, no severe adverse events were reported.

LDN treatment

• Test doses for Fibromyalgia: 0.75-6 mg (increments of 0.75 mg) since LDN primarily influences the hyperalgesia, fatigue and sleep "...which secondarily influences pain
• Can also be used to affect Complex Regional Pain Syndrome (CRPS) via sensory or autonomic nervous disorder.

Monitoring Parameters

• Monitoring is important which can include Erythrocyte Sedimentation Rate to ascertain initial pilot of LDN in fibromyalgia this will help determine if the treatment if ESR is related and individuals with greater ESR at baseline experienced a greater drop in pain and if FM values were in the normal to high-normal range."
• ESR is a commonly performed hematology test and Indicator.

Normal ESR Range

• Which is defined as: Male <50 years old: ≤15 mm/hr, Female <50 years old: ≤ 20 mm/hr, Male >50 years old: ≤20 mm/hr, Female >50 years old: ≤30 mm/hr, Child: ≤10 mm/hr [38] although they typically has an Increase in females than males and also increases gradually with age
• Or: Interleukin 6 which helps promptly and transiently produced tissue injuries, contributes to host defense through the stimulation of acute phase responses, hematopoiesis, and immune reactions with Normal levels: 0 to 1.8 pg/mL whilst ESR or IL-6 can be used as an indicator
• And Symptom relief is the typical monitoring parameter used by most practitioners.
• Other treatments are magnesium which involves NO direct analgesic effect and help Prevent central sensitization to helps prevent central sensitization caused by peripheral tissue injury by Inhibiting calcium ions entering cells by blocking NMDA receptors (this is because It has been estimated that 10-30% of the population subclinical hypomagnesemia

Prevalence of Hypomagnesemia

• Which means that Mg serum level is below 0.8 mmol/L and and and was discovered during discovery was a possible public health concern for older adults since magnesium deficency Is linked to central sensitization and also Magnesium can reduce NMDA receptor linked pain,
• SideEffects include the blockade of NMDA and also blocks NMDA receptors in a voltage-dependent manner which will then lead to preventing development of central sensitization and abolish established hypersensitivity” in Neuropathic Pain

Magnesium in Chronic Low Back Pain

• Our findings show that a 2-week intravenous magnesium infusion followed by 4 weeks of oral magnesium supplementation can reduce pain intensity and improve lumbar spine mobility during a 6-month period in patients with refractory chronic low back pain with a neuropathic component."
• Also For Surgical Pain and Post Operative Sore Throat (POST) administration of oral magnesium before and after surgery showed lower pain intensity where administration of a single dose of oral magnesium could reduce the incidence and attenuate the severity of POST
• For other treamtents or suplements you have: Methylene Blue for Pain which downregulates NO synthase (INOS) and then lead to less nitric oxide release
• This process will then induce Reduced inflammation!! as it reduces voltage-gated sodium currents in neurons and firing rates in afferent nerve fibers which means the treatment may lead to reduced neuronal excitability

Low dose Methylene Blue

• Dosage should be titrated and individualized from 5-30 mg titrate which is most common every 2-3 days is considered is less than 2 mg/kg since at a Toxic at doses of 5mg/kg or higher.
• Administration with The maximum plasma concentration was reached at 2 hours with Plasma half-life is approximately 20 hou
• There is aslo Vitamin D3 and Systemic lupus erythematosus which has Elevated levels of memory B cells and so that May be related to neuropathy and the development of lymphoma
• Or as a Vitamin D serum deficiency or insufficiency , can be given to patients with Ankylosing spondylitis, Psoriatic arthritis (PsA) which includes Idiopathic inflammatory myopathies and Polymyalgia rheumatica including Rheumatoid arthritis and Systemic sclerosis
  • Which also alleviates Reduced muscle strength, Increase Pain which includes Fatigue and Higher diseas

D3 - Estrogen

• "Estrogen has been demonstrated to enhance vitamin D function favoring its accumulation, and increasing the expression of vitamin D receptor, thus resulting in a more potent anti-inflammatory response in females than males.
• The other hand, vitamin D has been shown to down regulate in immune cells the expression of aromatase, which converts testosterone to estrogen, leading to a decrease in estrogen level for which overall, available data allow us to hypothesize a higher protective effect of vitamin D-based therapeutic approaches in women, at least in fertile age, than in men.

What about the Coimbra Protocol

• For Vitamin D3 Resistance with Other supplements to consider are: Calcium because. Coimbra Protocol concerns, Hypercalcemia and or Impaired renal function and then Monitor Mean vitamin D3 dose was 35,291 ± 21,791 IU per day We found a very weak relationship between the dosage of oral vitamin D3 and the subsequent calcium levels, both in serum and in urinary excretion over 24 h, respectively."
• Although the protocol includes other supplements besides vitamin D, achieving the correct level of vitamin D for each patient accounts for 95%
• To achieve such results start in the beginning of treatment, PTH levels are initially measured, and then measured regularly during the treatment because if PTH is not at its minimum normal limit, vitamin D daily doses are increased until the desired PTH level is achieved
• During the treatment, PTH levels are expected to go down to their lowest normal limit since, When this happens, the resistance to vitamin D is overcome and the patient starts benefiting from its powerful immonodulatory effect
• From these findings It usually takes two years to adjust the doses of vitamin D and After this period, the treatment consists in maintenance of the proper levels of PTH and calcium.

GLP-1 Clinical Effects

• Can help with weight loss and so much more whic for example can be implemented during Evoke trial which is a ongoing trial, semaglutide oral, 14 mg QD With an expected results in of 2026 that is reverses cognitive impairment in mice, it’s therefore said that : Dual GLP-1/GIP RA may be - Superior to liraglutide in mouse model of AD (DA4-JC) and so Also Triple GLP-1/GIP/glucagon RA could be what protects your neuroprotection in mouse model of AD
• Can be implemented to help with Parkinson's Disease which may includes Lixisenatide as treatment with 78 pts in treatment group, ages 40-75 (12-month. intervention and daily injections

What can be implemented for Neurotherapy

• Increase intake by: Magnesium Glycinate and Chelate [400800mg BID] and Alpha Lipoic acid [250 −600 mg BID] which may include: Reduce plasma levels of interleukin 6 and increasing amounts of glutathione and reduce pain numbness and also or paresthesias"
• Other thing to keep and or have in mind to is Contradictions To keep you and and what and those with: Liver , Consuming alcohol or for large amounts Those with thyroid disease and or Thiamine as well those who are Deficient (ALA is known to lower blood sugar) , as well are Diabetic

For inflammatory help:

• What lifestyle changes can help to make it to a better improved inflammatory pain which include: Having the an anti , Inflammatory Diet which also means Adequately Sleeping And maintaining A Healthy Weight and or Regular Exercise but also you can use. Curcumin which binds to toll-like receptors and regulate the Janus kinase and inflammatory signaling pathways .Dosage: 200–500mg BID. Also Stop Smoking can Drink Alcohol Moderately.