Accurate Education – Naltrexone for Pain

Complementary and Alternative Medicine (CAM):

Naltrexone for Pain

 

 

Under Construction 

 

 

 

 

 

Hyperalgesia

Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally painful.

 

Also see:

Opioids

Opioid Induced Hyperalgesia (OIH)

Withdrawal-Induced Hyperalgesia (WIH)

Opioid Tolerance

Neurobiology of Pain

Neuropathic Pain

Gabapentin (Neurontin) & Pregabalin (Lyrica)

 

 

Definitions and Terms Related to Pain

 

Key to Links:

• Grey text – handout
• Red text – another page on this website
• Blue text – Journal publication

 

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Please note: This page is still pending further development

 

Naltrexone for Pain

Toll-like receptors (TLRs) play a key role in the immune system by responding to pathogen-associated molecular patterns (PAMPs) such as lipopolysaccharide (LPS) that are expressed on infectious agents such as bacteria and viruses. In particular, the TLR-4 receptors stimulate the production of proteins (cytokines) including the inflammatory modulators TNF-α and interleukin-1 that are key players in immune response.

 

The stimulation of these TLR-4 receptors is believed to contribute to neuropathic pain and the expression of central sensitivity, hyperalgesia (hypersensitivity to painful stimuli), and allodynia (the perception of pain as the result of a non-painful stimulus). These conditions are associated with painful diagnoses including fibromyalgia, migraine headaches, chronic low back pain, TMJ syndrome, interstitial cystitis and endometriosis. TLR-4 receptors are also believed to be involved in opioid-induced hyperalgesia (OIH) and withdrawal-induced hyperalgesia (WIH).

See Neurobiology of Pain

 

Opioids

Opioids are well known to be effective for pain of all types, though somewhat less so for neuropathic pain. Their effectiveness for pain is based on their activity of stimulating opioid receptors, most importantly the mu-opioid receptor (See Opioids). However, opioids also activate specific TLRs such as  TLR-4 which  leads to the release of inflammatory modulators including TNF-α and interleukin-1. Constant low-level release of these modulators is thought to reduce the effectiveness of opioids for paint with time and to be involved in both the development of opioid analgesic tolerancs and in the emergence of oioid-induced hypersensitivity to pain.

 

Morphine‐3‐glucuronide (M3G), a liver metabolite (breakdown product) of morphine, increases neuronal excitability via Toll‐like receptors (TLR). Morphine activation of TLR4, concentrated in spinal glial cells causes the release of inflammatory proteins (interleukin‐1, and tumor necrosis factor (TNF‐α), that result in neuroinflammation and increased pain. It is believed that M3G is a significant contributor to the side effects of morphine and that individual variants, genetic-based or otherwise, lead to greater M3G levels in some patients causing greater intolerance of morphine. This can be especially true in patients with compromised renal function which leads to reduced elimination of M3G and greater symptoms of toxicity.

 

Opioid Antagonists

Opioid antagonists that have the opposite effect of opioids by blocking the activity of opioids are now being explored for new applications in pain management. Certain opioid antagonists (actually reverse agonists), including naloxone and naltrexone, not only function to block opioid activity at opioid receptors but they also block or antagonize activity at the TLR-4 receptors as well. This is believed to reduce the neuroinflammation triggered by TLR-4 and may be of benefit in the treatment of the neuropathic pain conditions described above. In fact, there is a growing body of research suggesting that low dose naltrexone may be effective for fibromyalgia and other conditions associated with central sensitivity.

See Naltrexone for Pain (coming soon)

 

Due to their antagonizing activity with opioids, ordinarily they cannot be given simultaneously with opioids unless at very low doses (<1 mg). However, research has shown that naloxone and naltrexone both exists as enatiomers, or both left- and right-handed versions that are molecular mirror images of one another much like a left or right handed glove. While typically medications are manufactured as combinations of both left- and right enatiomers in equal distributions, it is possible to isolate the left- from the right- enatiomer. Chemically identical but structurally different, the right (dextro) version of naltrexone antagonizes activity of TLR-4 but has no affinity for, and does not affect, opioid receptors. Thus, the dextro enantiomer of naltrexone may be effective in treating pain by blocking TLR-4 while not affecting the opioid receptors, thereby avoiding adverse effects associated with blocking the opioid receptors. This discovery represents a potentially useful breakthru in the management of neuropathic pain and related syndromes. 

Resources:

LDN Research Trust.org

Reference Articles:

 

Naltrexone for Pain – Recent Uploads

1. Association of low-dose naltrexone and transcranial direct current stimulation in fibromyalgia- – 2022
2. Low-Dose Naltrexone (LDN) for Chronic Pain at a Single Institution- A Case Series – 2023
3. Low-dose naltrexone’s utility for non-cancer centralized pain conditions- a scoping review – 2023
4. Low-dose naltrexone for treatment of pain in patients with fibromyalgia- a randomized, double-blind, placebo-controlled, crossover study – 2023
5. The Safety and Efficacy of Low-Dose Naltrexone in Patients with Fibromyalgia- A Systematic Review – 2023
6. Efficacy of Low-Dose Naltrexone and Predictors of Treatment Success or Discontinuation in Fibromyalgia and Other Chronic Pain Conditions – 2023
7. A systematic literature review on the clinical efficacy of low dose naltrexone and its effect on putative pathophysiological mechanisms among patients diagnosed with fibromyalgia – 2023
8. Opiate Antagonists for Chronic Pain- A Review on the Benefits of Low-Dose Naltrexone in Arthritis versus Non-Arthritic Diseases – 2023
9. Low-Dose Naltrexone Use for Patients with Chronic Regional Pain Syndrome- A Systematic Literature Review – 2021
10. Depression in Fibromyalgia Patients May Require Low-Dose Naltrexone to Respond- A Case Report – 2022
11. Low-Dose Naltrexone Co-Treatment in the Prevention of Opioid-Induced Hyperalgesia – 2021
12. Sjogren’s Syndrome and Clinical Benefits of Low-Dose Naltrexone Therapy_ Additional Case Reports – PubMed – 2020
13. Effective Doses of Low-Dose Naltrexone for Chronic Pain – An Observational Study – 2024
14. Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia- A Randomized, Controlled Trial of Oxytrex – 2005
15. Low-Dose Naltrexone Usage in Multiple Sclerosis _ National MS Society
16. Potential Therapeutic Benefit of Low Dose Naltrexone in Myalgic Encephalomyelitis_Chronic Fatigue Syndrome_ Role of Transient Receptor Potential – PubMed- 2021

 

Naltrexone for Pain – Overviews

1. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone
2. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. 2014
3. Aversive effects of naltrexone in subjects not dependent on opiates. – PubMed – NCBI

Naltrexone – Opioid Tolerance and Dependence

1. Ultra-low-dose opioid antagonists enhance opioid analgesia while reducing tolerance, dependence and addictive properties
2. Ultra Low Dose Naltrexone – For Lower Opiate Tolerance – Research Summary

 

Naltrexone – Inflammatory Bowel Disease (Chrohns & Ulcerative Colitis)

1. Therapy with the Opioid Antagonist Naltrexone Promotes Mucosal Healing in Active Crohn’s Disease – A Randomized Placebo-Controlled Trial – 2011
2. Low dose naltrexone for induction of remission in Crohn’s disease (Cochrane Review)-2018
3. Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease – 2007

 

Naltrexone – Interstitial Cystitis & Systemic Inflammation

1. Inflammation and Inflammatory Control in Interstitial Cystitis: Bladder Pain Syndrome – Associations with Painful Symptoms – 2014
2. Inflammation and Symptom Change in Interstitial Cystitis: Bladder Pain Syndrome – A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study – 2016
3. Toll-like Receptor 4 and Comorbid Pain in Interstitial Cystitis: Bladder Pain Syndrome – A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Study – 2015
4. Inflammation and central pain sensitization in Interstitial Cystitis:Bladder Pain Syndrome – 2015

Emphasis on Education

 

Accurate Clinic promotes patient education as the foundation of it’s medical care. In Dr. Ehlenberger’s integrative approach to patient care, including conventional and complementary and alternative medical (CAM) treatments, he may encourage or provide advice about the use of supplements. However, the specifics of choice of supplement, dosing and duration of treatment should be individualized through discussion with Dr. Ehlenberger. The following information and reference articles are presented to provide the reader with some of the latest research to facilitate evidence-based, informed decisions regarding the use of conventional as well as CAM treatments.

 

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