Accurate Education – Naltrexone Treatment Protocols

Naltrexone for Pain:

Naltrexone Treatment Protocols

The use of naltrexone in pain management has gained important attention as an alternative means of treating certain pain conditions otherwise resistant to successful pain control, including opioid induced hyperalgesia (OIH), Opioid Analgesic Tolerance (OAT), fibromyalgia and other conditions.

 

 Key Terms:

Neuropathic pain (“Nerve Pain”)

Neuropathic pain is defined as “pain arising as a direct consequence of a lesion or disease affecting the nervous system.”  Neuropathic Pain is often a disease process, not simply the symptom of one.

Nerve pain is usually perceived as burning, electric, shock-like, tingling or sharp and may start at one location and shoot, or “radiate” to another location (like sciatica). Neuropathic pain can be “peripheral,”  (outside the central nervous system),”  like carpal tunnel pain or “central,” originating in the spinal cord or brain.

Hyperalgesia

Hyperalgesia is an exaggerated, increased painful response to a stimulus which is normally (less) painful. Is often associated with neuropathic pain, and central sensitization.

Allodynia:

Allodynia is a term that describes the experience of pain from a stimulus which does not normally provoke pain. An example is a someone with diabetic neuropathy whose feet are sensitive and they feel discomfort or pain with  light touch such as putting on socks.

Like hyperalgesia, allodynia can be a consequence of central sensitization which commonly accompanies fibromyalgia, diabetic neuropathy and chronic headaches and other neuropathic pain conditions.

Opioid-Induced Hyperalgesia (OIH)

OIH is a condition where your body becomes more sensitive to pain because of long-term opioid use. Instead of helping, opioids can sometimes make pain worse or cause new pain in different areas.The prevalence of OIH in patients on long-term opioid therapy is likely in the range of 5% to 15%,.

Opioid Analgesic Tolerance (OAT)

When one has taken opioids at high doses or for a prolonged period of time, one may need higher doses to get the same pain relief, defined as Opioid Analgesic Tolerance (OAT). This is different from OIH, but both can occur together. The expected prevalence of clinically significant opioid analgesic tolerance is very high—likely >50% and approaches 100% of patients with increasing duration of therapy. It is considered a normal physiological response to the use of opioids.

Central Sensitization (CS)

Central sensitization (CS) is when your nervous system becomes extra-sensitive, making you feel pain more easily or more intensely (hyperalgesia), even from things that shouldn’t hurt at all (allodynia). This is common in conditions like migraines, chronic back pain, neuropathy and fibromyalgia and it can be worsened by long-term opioid use.

 

Also see:

• Naltrexone for Pain
• Opioid Induced Hyperalgesia (OIH)
• Opioid Analgesic Tolerance
• Central Sensitization
• Opioids
• Withdrawal-Induced Hyperalgesia (WIH)
• Neurobiology of Pain
• Neuropathic Pain
  

 

Definitions and Terms Related to Pain

 

Key to Links:

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• Endogenous Opioid Tone

 

 

Naltrexone  – The Old and The New 

Naltrexone (Vivitrol, Revia) is a semi-synthetic opioid developed in the 1960s and first approved by the FDA in 1984 for the treatment of opioid use disorder (OUD) and subsequently approved for alcohol dependency in 1994. It is prescribed for these conditions in the range of 50 to 100 mg doses. Because its drug safety profile is well established at these high doses, naltrexone taken at much lower doses is generally safe and can also be considered for other clinical conditions even while taking opioids simultaneously.

Recently, the use of naltrexone in pain management has gained attention as an alternative means of treating certain pain conditions otherwise resistant to good pain control, including opioid induced hyperalgesia (OIH), opioid analgesic tolerance (OAT) and various chsroni pain conditions.

Naltrexone

Naltrexone is structurally and functionally similar to the opioid antagonist naloxone (Narcan), but it has a longer half-life and better bioavailability. It is an opioid antagonist that blocks the analgesic and euphoric effects of opioids.

Naltrexone exhibits an uncommon biphasic dose response: it works differently at high doses than at low doses. Consequently, low-dose naltrexone (LDN) in doses ranging from 1 to 6 mg provides anti-inflammatory effects that reduce pain and  central sensitization. Ultra low dose naltrexone (ULDN), doses below 0.01 mg, provides a unique mechanism that higher doses do not provide and may be useful in treating opioid-induced hyperalgesia (OIH).

 

 

Naltrexone – Treatment of OIH, OAT, and CS

Background and Rationale

Opioid analgesic tolerance (OAT) and opioid-induced hyperalgesia (OIH) are major clinical challenges in chronic pain management that impair successful control of pain. This section reviews methods of combating these two conditions in order to improve pain management, with a focus of the use of naltrexone. Naltrexone can be used in two different treatment protocols two reduce OAT and OIH.

1. Opioid Analgesic Tolerance (OAT)

OAT is a physiological adaptation in which repeated use of opioids leads to a decreased response to the drug’s effects. As a result, a higher or more frequent dose of the opioid is required to achieve the same level of pain relief or other desired effects.  There are multiple mechanisms by which OAT develops.

1. 1. Receptor desensitization and internalization: Opioids produce their effects by binding to opioid receptors, primarily the mu-opioid receptors, on the surface of a nerve cell. With chronic use, these receptors become less responsive (desensitization) and are pulled inside the cell (internalization), reducing their number on the cell’s surface thereby decreasing the cell’s response to opioids.
   2. Increased counter-regulatory systems: The nervous system activates counteracting mechanisms to restore balance. One such system involves the N-methyl-D-aspartate (NMDA) receptors. Chronic opioid use enhances NMDA receptor function, leading to increased levels of calcium and nitric oxide within the cells, which can reduce the effectiveness of opioids.
   3. Hyperactivation of the cAMP pathway: Opioids normally inhibit the production of cyclic adenosine monophosphate (cAMP). With long-term use, the system undergoes an adaptation that leads to an increased, or “super-activated,” level of cAMP production, effectively opposing the opioid’s action.
   4. Neuroimmune activation: The immune system in the central nervous system, particularly glial cells, can become activated by chronic opioid use. This neuro-inflammation contributes to the development of tolerance and opioid-induced hyperalgesia (increased pain sensitivity).

 

2. Opioid-Induced Hyperalgesia (OIH)

OIH is a condition where your body becomes more sensitive to pain due to long-term opioid use. Instead of helping, opioids can sometimes make pain worse or cause new pain in different areas. The prevalence of OIH in patients on long-term opioid therapy is estimated to occur in  5% to 15% of patients.

In OIH, chronic opioid use leads to changes in some of the nerve receptors (mu-opioid receptors [MOR]) that opioids attached to that normally triggers a process that leads to reduced pain. One of these critical changes involves a protein that couples with the MOR, specifically a shift from an inhibitory Gi/o protein to an excitatory Gs protein. This change to the excitatory Gs protein coupling causes both increased OAT and OIH that manifests as reduced pain benefit from opioids and increased pain sensitivity. These processes are further amplified by neuro-inflammation and glial activation.[1][2][3]

Treatment of OAT and OIH with Naltrexone

Recently, the use of naltrexone in pain management has show effectiveness for treating some pain conditions that have demonstrated resistance to good pain control, including OIH, low back pain, diabetic neuropathy, rheumatoid arthritis, inflammatory bowel diseases, chronic regional pain syndrome (CRPS), fibromyalgia and other conditions.

Naltrexone is structurally and functionally similar to the opioid antagonist naloxone (Narcan), but it has a longer half-life and better bioavailability. It is an opioid antagonist that blocks the analgesic and euphoric effects of opioids. The key to understanding the use of naltrexone to reduce OAT and OIH is that the dosing for these conditions is of much less magnitude so that the naltrexone does not impact the concurrent use of opioids being used to treat pain and does not require reduction or changing of these opioids.

The dosing for treating OAT and OIH is also a magnitude of difference, including Ultra-Low-Dose Naltrexone (ULDN) and Low-dose Naltrexone (LDN). Both ULDN and LDN have emerged as  two separate strategies to suppress or prevent OAT and OIH.

ULDN vs LDN

Ultra-low-dose naltrexone (ULDN) dosing is in the range of 0.001 to 0.01 mg (1-10 mcg) per day while low-dose naltrexone (LDN) is in the range of 0.1 to 4.5 mg per day. These two dosing strategies have different mechanisms of action and different effectiveness (efficacy) profiles.

ULDN

When combined with chronic opioid therapy, ULDN demonstrates greater effectiveness than LDN in suppressing opioid tolerance and opioid-induced hyperalgesia (OIH), while both regimens are safe and well tolerated. However, direct head-to-head clinical trial comparisons between ULDN and LDN are lacking; available evidence comes from separate studies and meta-analyses.

ULDN (Ultra-low-dose naltrexone) in the dosing range of 0.001 to 0.01 mg (1-10mcg)  per day.

ULDN is significantly more effective at suppressing Gs protein coupling at the mu-opioid receptor than low-dose naltrexone (LDN).

Preclinical studies demonstrate that ULDN prevents the shift of opioid receptor signaling from inhibitory Gi/o to excitatory Gs coupling, thereby reducing opioid-induced hyperalgesia and tolerance. This effect is dose-dependent and unique to the ultra-low range; higher doses (such as those used in LDN protocols) do not selectively block Gs coupling and instead produce broader opioid receptor antagonism and immunomodulatory effects.

LDN (0.1–4.5 mg/day)

LDN transiently blocks opioid receptors, leading to increased endogenous opioid production (β-endorphins, enkephalins). This process of increasing endogenous opioid tone suppress the shift from inhibitory Gi/o to excitatory Gs coupling thereby reducing OIH, However, these doses do not specifically suppress Gs protein coupling at the opioid receptor as effectively as ULDN.

LDN has long been thought to relieve pain with rebound increase in endogenous opioids after temporary opioid receptor blockade, but one recent study has cast doubt on this proposed mechanism of action, finding no evidence of LDN’s effect on opioid receptor sensitivity, production of β-endorphin precursor or β-endorphin release in the plasma. Confirmation of this finding is still needed.

This may leave TLR4 inhibition as the most significant mechanism of action for analgesia with LDN. Evidence strongly supports the analgesic role that LDN plays in blocking TLR4 receptors that results in significant anti-inflammatory effects by modifying glial cell activity.

LDN also increases the number of opioid receptors. [2][3][4][5][6]

The clinical and mechanistic literature consistently distinguishes ULDN’s unique ability to prevent maladaptive G-protein signaling and opioid tolerance from the broader effects of LDN.[1]

Clinical Evidence for ULDN Treatment with Concurrent Opioid Therapy

Randomized controlled trials and preclinical studies consistently show that co-administration of ULDN concurrently with opioids (notably oxycodone and morphine) enhances analgesia, reduces the development of tolerance, and minimizes physical dependence.[1][2][3][4][5][6][7][8][9]

In the Oxytrex trials of a research drug, patients receiving oxycodone plus ULDN (1–2 μg naltrexone per dose, twice a day) experienced greater pain relief, less dose escalation, and fewer withdrawal symptoms compared to those taking oxycodone alone.[1][3][4] ULDN also improved side effects, with reductions in the constipation, drowsiness, and itching associated with oxycodone and morphine.[4]

Efficacy of ULDN for Oat and OIH:

ULDN (doses in the microgram range ( 0.002–0.004 mg/day):

• Randomized controlled trials of Oxytrex (oxycodone + ULDN) show that ULDN significantly enhances and prolongs opioid analgesia, reduces the development of tolerance, and improves pain control compared to oxycodone alone. The mechanism is prevention of aberrant G-protein (Gs) coupling at the mu-opioid receptor, which underlies tolerance and OIH.[1][2]
• Treatment with ULDN has been shown in preclinical studies to minimize physical dependence and it has demonstrated fewer withdrawal symptoms and reduced incidence of common opioid side effects,
• Preclinical studies confirm that ULDN co-administered with opioids augments analgesia, inhibits tolerance, and reverses established tolerance and hyperalgesia, with effects believed to be mediated by both opioid receptor and possibly TLR4 blockade.[3][4][5][6][7]
• ULDN also attenuates opioid-induced glial activation, further supporting its role in minimizing tolerance and OIH.[4]
• OIH symptoms can improve rapidly (average 8 days) with effective intervention, but recurrence is expected if the underlying opioid dosing is maintained and naltrexone therapy is discontinued.

ULDN Recommended Dosing Strategies and Protocols

The only clinical study protocol was used in Oxytrex studies with ULDN at 0.002–0.004 mg/day (1–2 μg per dose, twice daily) combined with standard oxycodone dosing,.[1][3][4]

Interestingly, Lower total daily doses (2 μg/day, bid) were found to be more effective than higher or more frequent dosing (4 μg/day, QID).[1][4] This approach was adapted for other opioid regimens and similar strategies were used in morphine/naltrexone formulations such as Embeda.[10]. In preclinical models, doses as low as 10–100 ng/kg have shown efficacy.[5][6]

It should be noted that Oxytrex was studied in patients with chronic pain who were not currently taking opioids. The study did not assess the reduction of pain relative to reducing OIH in patients on chronic opioid therapy, although the findings do suggest the possibility of reducing the development of OIH.

In fact, there are no human studies in which treatment with ULDN has been assessed for effectiveness in treating OIH. Therefore, the use of ULDN for treating OIH should be considered investigational and off-label.

Mechanistic Summary of ULDN

ULDN prevents the shift from inhibitory Gi/o to excitatory Gs coupling at the MOR, thereby attenuating the neuroplastic changes that underlie tolerance and OIH.[2][5][6] It also reduces glial activation and blocks TLR4-mediated neuroinflammation, further supporting its role in minimizing opioid-induced maladaptation.[2][11][12] These effects have been confirmed in both animal and cellular studies.[5][6][11][12]

Safety and Adverse Effects

ULDN does not increase the risk of opioid withdrawal or adverse events compared to opioid monotherapy.[1][3][4] The incidence of common opioid side effects is reduced, and no significant safety concerns have been reported at these ultra-low doses. The safety of LDN has been established and given the markedly lower dose of ULDN vs. LDN, significant safety concerns would not be expected, but nevertheless studies, including long-term effects, have not been performed.

Summary: The recommended protocol for minimizing opioid tolerance and OIH is to combine ULDN (1–2 μg per dose, bid; total 0.002–0.004 mg/day) with standard opioid therapy. This regimen is supported by robust preclinical and mechanistic evidence for enhanced analgesia, reduced tolerance, and safety, although no clinical studies have yet been performed. [1][2][3][4][5][6][7][8][9][10][11][12]

References

1. Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex. Chindalore VL, Craven RA, Yu KP, et al. The Journal of Pain. 2005;6(6):392-9. doi:10.1016/j.jpain.2005.01.356.
2. Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated Mu-Opioid Receptor-Gs Coupling. Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. The Journal of Pain. 2008;9(8):700-13. doi:10.1016/j.jpain.2008.03.005.
3. Oxytrex: An Oxycodone and Ultra-Low-Dose Naltrexone Formulation. Webster LR. Expert Opinion on Investigational Drugs. 2007;16(8):1277-83. doi:10.1517/13543784.16.8.1277.
4. Oxytrex Minimizes Physical Dependence While Providing Effective Analgesia: A Randomized Controlled Trial in Low Back Pain. Webster LR, Butera PG, Moran LV, et al. The Journal of Pain. 2006;7(12):937-46. doi:10.1016/j.jpain.2006.05.005.
5. Ultra-Low Doses of Naltrexone or Etorphine Increase Morphine’s Antinociceptive Potency and Attenuate Tolerance/Dependence in Mice. Shen KF, Crain SM. Brain Research. 1997;757(2):176-90. doi:10.1016/s0006-8993(97)00197-2.
6. Paradoxical Effects of the Opioid Antagonist Naltrexone on Morphine Analgesia, Tolerance, and Reward in Rats. Powell KJ, Abul-Husn NS, Jhamandas A, et al. The Journal of Pharmacology and Experimental Therapeutics. 2002;300(2):588-96. doi:10.1124/jpet.300.2.588.
7. Dissociable Effects of Ultralow-Dose Naltrexone on Tolerance to the Antinociceptive and Cataleptic Effects of Morphine. Tuerke KJ, Beninger RJ, Paquette JJ, Olmstead MC. Behavioural Pharmacology. 2011;22(5-6):558-63. doi:10.1097/FBP.0b013e3283474a56.
8. Ultra-Low-Dose Naltrexone Suppresses Rewarding Effects of Opiates and Aversive Effects of Opiate Withdrawal in Rats. Olmstead MC, Burns LH. Psychopharmacology. 2005;181(3):576-81. doi:10.1007/s00213-005-0022-7.
9. Ultra-Low-Dose Naltrexone Reduces the Rewarding Potency of Oxycodone and Relapse Vulnerability in Rats. Leri F, Burns LH. Pharmacology, Biochemistry, and Behavior. 2005;82(2):252-62. doi:10.1016/j.pbb.2005.08.008.
10. FDA Orange Book. FDA Orange Book.
11. Ultra-Low Dose Naltrexone Attenuates Chronic Morphine-Induced Gliosis in Rats. Mattioli TA, Milne B, Cahill CM. Molecular Pain. 2010;6:22. doi:10.1186/1744-8069-6-22.
12. Antinociceptive Effect of Ultra-Low Dose Naltrexone in a Pre-Clinical Model of Postoperative Orofacial Pain. Hummig W, Baggio DF, Lopes RV, et al. Brain Research. 2023;1798:148154. doi:10.1016/j.brainres.2022.148154.

 

LDN (doses 0.1–4.5 mg/day):

• LDN is effective for improving pain and pain tolerance in patients with OIH and fibromyalgia, as shown in open-label clinical series and meta-analyses. LDN quadrupled pain tolerance in OIH patients (cold pressor test) and doubled it in fibromyalgia, with large effect sizes.[8][9][10][11][12]
• LDN’s primary mechanism is modulation of neuroinflammation and glial cell activity, rather than direct suppression of Gs protein coupling. It is most effective for centralized pain syndromes and may help correct OIH, but its impact on opioid tolerance is less pronounced than ULDN.[9][10][11]
• Meta-analysis shows LDN is superior to placebo for pain reduction in fibromyalgia, but not significantly different from active comparators in other chronic pain syndromes.[11]

Safety

Both ULDN and LDN are well tolerated, with adverse event rates similar to placebo or active comparators. ULDN does not increase withdrawal risk or opioid side effects when combined with opioids. LDN may cause mild nausea, headaches, and vivid dreams, but serious adverse events are rare.[1][2][11][12]

Summary:

• Based o preclinical studies, ULDN is superior for preventing opioid tolerance and OIH when combined with chronic opioid therapy, while LDN is effective for improving pain and pain tolerance, especially in centralized pain syndromes.
• Both regimens are safe, but direct comparative trials are needed.
• ULDN may be considered for patients at high risk of tolerance or OIH
• LDN is suggested for refractory pain associated with many chronic pain conditions.

References

1. Adding Ultralow-Dose Naltrexone to Oxycodone Enhances and Prolongs Analgesia: A Randomized, Controlled Trial of Oxytrex. Chindalore VL, Craven RA, Yu KP, et al. The Journal of Pain. 2005;6(6):392-9. doi:10.1016/j.jpain.2005.01.356.
2. Oxytrex: An Oxycodone and Ultra-Low-Dose Naltrexone Formulation. Webster LR. Expert Opinion on Investigational Drugs. 2007;16(8):1277-83. doi:10.1517/13543784.16.8.1277.
3. Antinociceptive Effect of Ultra-Low Dose Naltrexone in a Pre-Clinical Model of Postoperative Orofacial Pain. Hummig W, Baggio DF, Lopes RV, et al. Brain Research. 2023;1798:148154. doi:10.1016/j.brainres.2022.148154.
4. Ultra-Low Dose Naltrexone Attenuates Chronic Morphine-Induced Gliosis in Rats. Mattioli TA, Milne B, Cahill CM. Molecular Pain. 2010;6:22. doi:10.1186/1744-8069-6-22.
5. Paradoxical Effects of the Opioid Antagonist Naltrexone on Morphine Analgesia, Tolerance, and Reward in Rats. Powell KJ, Abul-Husn NS, Jhamandas A, et al. The Journal of Pharmacology and Experimental Therapeutics. 2002;300(2):588-96. doi:10.1124/jpet.300.2.588.
6. Dissociable Effects of Ultralow-Dose Naltrexone on Tolerance to the Antinociceptive and Cataleptic Effects of Morphine. Tuerke KJ, Beninger RJ, Paquette JJ, Olmstead MC. Behavioural Pharmacology. 2011;22(5-6):558-63. doi:10.1097/FBP.0b013e3283474a56.
7. Ultra-Low-Dose Naltrexone Suppresses Rewarding Effects of Opiates and Aversive Effects of Opiate Withdrawal in Rats. Olmstead MC, Burns LH. Psychopharmacology. 2005;181(3):576-81. doi:10.1007/s00213-005-0022-7.
8. The Effects of Low Dose Naltrexone on Opioid Induced Hyperalgesia and Fibromyalgia. Jackson D, Singh S, Zhang-James Y, Faraone S, Johnson B. Frontiers in Psychiatry. 2021;12:593842. doi:10.3389/fpsyt.2021.593842.
9. Low-Dose Naltrexone’s Utility for Non-Cancer Centralized Pain Conditions: A Scoping Review. Rupp A, Young E, Chadwick AL. Pain Medicine (Malden, Mass.). 2023;24(11):1270-1281. doi:10.1093/pm/pnad074.
10. Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review. Kim PS, Fishman MA. Current Pain and Headache Reports. 2020;24(10):64. doi:10.1007/s11916-020-00898-0.
11. Low Dose Naltrexone in the Management of Chronic Pain Syndrome: A Meta-Analysis of Randomized Controlled Clinical Trials. Hegde NC, Mishra A, V D, et al. Current Pain and Headache Reports. 2025;29(1):96. doi:10.1007/s11916-025-01411-1.
12. The Utilization of Low Dose Naltrexone for Chronic Pain. Poliwoda S, Noss B, Truong GTD, et al. CNS Drugs. 2023;37(8):663-670. doi:10.1007/s40263-023-01018-3.

Patient Selection Criteria: ULDN vs. LDN

Selection for ULDN or LDN in chronic opioid therapy should begin with a thorough review of opioid history, including type, duration, and daily morphine equivalent dosing. Patients on high daily doses and/or long-term opioid management are at greatest risk for opioid-induced hyperalgesia (OIH) and should be prioritized for assessment targeting initiation of ULDN.

It is recommended to assess for any poorly controlled psychiatric co-morbidities, sleep problems and overall quality of life, as these factors may influence response to therapy and may need to be addressed.

Initiation of ULDN

Consider initiation of ultra-low-dose naltrexone (ULDN, 1–2 μg twice daily (total dose: 0.002–0.004 mg/day) in patients with:

• High opioid doses (especially >200 ME/day)
• Calculate: “morphine years” described as daily use for a year at 60 MME.
• Cold pressor testing (CPT) with evidence of OIH
• Use of opioids with high Gs-coupling risk (e.g., oxycodone, morphine, fentanyl patches)
• History of escalating opioid dosing
• History of poor response to increased opioid dosing
• New allodynia or unexplained development of pain outside the original pain area
• Symptoms of central sensitization, elevated CSI scores
• Include standardized, neuropathic pain questionnaires, and central sensitive inventory (CSI)

Initiation and Monitoring

1. Initiate treatment with 1 mcg (one microgram) twice/day
2. If no clinical benefit is observed after 4 weeks @ 1 mcg twice/day, increase dose to 2 mcg twice/day
3. If no clinical benefit is observed after 4 weeks @ 2 mcg twice/day, consider transitioning to LDN or discontinue ULDN.
4. If good clinical benefit is observed @ 1-2 mcg twice/day, maintain current dosing

ULDN Maintenance Treatment

• There is no standardized duration for ultra-low-dose naltrexone (ULDN) therapy in patients with opioid-induced hyperalgesia (OIH); most studies recommend maintaining ULDN as long as pain control is improved and OIH symptoms are controlled.
• A large cohort study found up to a 46% annual reduction in opioid consumption among patients who continued naltrexone therapy. Treatment with ULDN is associated with the largest decrease in opioid dose among other OIH management strategies, often with rapid improvement (mean: 8 days).
• When continuing chronic opioid pain management, intermittent short acting opioids may be preferred to long acting or time-release opioids to reduce risk of OIH recurrence.
• Opioid rotation—switching to agents like buprenorphine can reduce OIH
• Tapering the opioid dose (10–20% reduction is recommended as tolerated to further reduce OIH recurrence risk.
• CAM supplements with mechanistic arguments for synergy or additive benefits are recommended (omega-3, curcumin, magnesium and others – (Handout – Central Sensitization Supplements)
• Regular reassessments such as the Central Sensation Inventory (CSI), Cold Pressor test (CPT), and DNIC/CPM are advised to guide ongoing therapy.
• Discontinuation of ULDN may be considered if pain tolerance normalizes, pain relief is sustained, and opioid dose is reduced without recurrence of OIH. However, recurrence of OIH is common when naltrexone treatment is discontinued.

Recurrence of OIH

• Chronic pain patients on high-dose, long-duration opioid therapy—especially those treated with potent full agonists such as oxycodone, morphine, fentanyl patches—are most likely to experience rapid recurrence of opioid-induced hyperalgesia (OIH) after discontinuing ULDN while remaining on opioid treatment.

• Patient with co-morbidities associated with impaired endogenous pain inhibition, including fibromyalgia and central sensitization syndromes, or reduced endogenous opioid tone (as measured by CPT or DNIC/CPM) are more vulnerable to OIH recurrence, as naltrexone’s benefit in restoring opioid tone is lost when therapy is stopped.

• Patients with severe baseline OIH symptoms or abnormal cold pressor test results

• Recurrence of symptoms is likely reoccur within 2–8 weeks after stopping ULDN, especially in high-risk patients who remain on opioids. This aligns with the time course for loss of ULDN’s anti-hyperalgesic and anti-inflammatory effects and re-emergence of central sensitization.

Initiation of LDN

LDN (1.5–4.5 mg/day) is a reasonable step, with expected response in 2–4 weeks and sustained benefit over months. LDN can significantly improve pain tolerance and reduce opioid requirements.

An open-label case series (not a randomized trial) found that LDN (1–4.5 mg/day) in patients with OIH quadrupled pain tolerance as suggested by abnormal cold pressor testing, with a large effect size (meaning the treatment is very effective) and statistical significance. However, this study did not include a control group or direct comparison to other interventions

It should be noted that treatment with LDN that is not co-administered with opioids may be effective as stand alone management for pain reduction in fibromyalgia and possibly other pain conditions although at this time, evidence is early. LDN is particularly effective for improving pain tolerance and quality of life in chronic pain syndromes, and may be considered as first-line in these populations.[5][8][11]

Patient Selection for Initiation of LDN treatment:

1. Patients with high risk of OIH if they have failed treatment with ULDN.
2. Patients on high dose or long-term chronic opioid management at apparent risk of OAT
3. Patients with likelihood of central sensitization or refractory centralized pain syndromes (fibromyalgia, CRPS, neuropathic pain)
4. Patients with neuropathic pain or other conditions seeking improved control of pain or other symptoms (see list below of conditions potentially likely to respond to LDN). [5][6][7][8][9][10][11]

Conditions with evidence for potential benefit with LDN:

• Rheumatoid arthritis
• Osteoarthritis
• Low back pain
• Diabetic Neuropathy
• Fibromyalgia
• Chronic Fatigue Syndrome
• Crohn’s Disease
• Multiple Sclerosis
• Ehlers Danlos Syndrome or Hypermobile Spectrum Disorder
• Chronic Regional Pain Syndrome (CRPS)
• Anxiety associated with chronic pain
• Depression associated with chronic pain

 

References

1. The Effects of Low Dose Naltrexone on Opioid Induced Hyperalgesia and Fibromyalgia. Jackson D, Singh S, Zhang-James Y, Faraone S, Johnson B. Frontiers in Psychiatry. 2021;12:593842. doi:10.3389/fpsyt.2021.593842.
2. Very Low Dose Naltrexone Addition in Opioid Detoxification: A Randomized, Controlled Trial. Mannelli P, Patkar AA, Peindl K, et al. Addiction Biology. 2009;14(2):204-13. doi:10.1111/j.1369-1600.2008.00119.x.
3. Oxycodone Plus Ultra-Low-Dose Naltrexone Attenuates Neuropathic Pain and Associated Mu-Opioid Receptor-Gs Coupling. Largent-Milnes TM, Guo W, Wang HY, Burns LH, Vanderah TW. The Journal of Pain. 2008;9(8):700-13. doi:10.1016/j.jpain.2008.03.005.
4. Pharmacological Interventions for Preventing Opioid-Induced Hyperalgesia in Adults After Opioid-Based Anesthesia: A Systematic Review and Network Meta-Analysis. Xie WJ, Hong JS, Feng CF, et al. Frontiers in Pharmacology. 2023;14:1199794. doi:10.3389/fphar.2023.1199794.
5. Pharmacological Interventions for Opioid-Induced Hyperalgesia: A Scoping Review of Preclinical Trials. Koponen ME, Forget P. Journal of Clinical Medicine. 2022;11(23):7060. doi:10.3390/jcm11237060.
6. Low Dose Naltrexone in the Management of Chronic Pain Syndrome: A Meta-Analysis of Randomized Controlled Clinical Trials. Hegde NC, Mishra A, V D, et al. Current Pain and Headache Reports. 2025;29(1):96. doi:10.1007/s11916-025-01411-1.
7. Low-Dose Naltrexone for Chronic Pain: Update and Systemic Review. Kim PS, Fishman MA. Current Pain and Headache Reports. 2020;24(10):64. doi:10.1007/s11916-020-00898-0.
8. Low-Dose Naltrexone’s Utility for Non-Cancer Centralized Pain Conditions: A Scoping Review. Rupp A, Young E, Chadwick AL. Pain Medicine (Malden, Mass.). 2023;24(11):1270-1281. doi:10.1093/pm/pnad074.
9. The Utilization of Low Dose Naltrexone for Chronic Pain. Poliwoda S, Noss B, Truong GTD, et al. CNS Drugs. 2023;37(8):663-670. doi:10.1007/s40263-023-01018-3.

 

Establishing the Maximum Effective Dose (MED)

It is recommended to very slowly increase LDN dosing in an effort to establish a maximum effective dose (MED).  Patients are advised that if LDN is effective they should notice diminished generalized pain, reduced exaggerated pain sensations (hyperalgesia), and/or increased mood and energy. If any of this responses occur, it signals the entry into a “window of effectiveness.”  Doses below or above this window may not be as effective.

Therefore, as patients initiate LDN, they are instructed to carefully monitor their response to each increase in dose and if 2 successive dose increases do not produce additional improvement, they are to go back to the dose prior to the last 2 increases which would be their MED. There is no specific dose or range that has been established as optimal. Most studies initiate LDN dosing with 1 or 1.5 mg per day, although lower doses may be used as well (0.1 – 1.0 mg/day).

The most common recommended initial regimen for low-dose naltrexone (LDN) is 1.5 mg once daily, titrated weekly by 1.5 mg increments up to a maximum of 4.5–6 mg daily, with dose escalation based on tolerability and clinical response. Once-daily evening dosing is preferred over twice-daily, as supported by recent randomized controlled trial protocols and dose-response studies.[1][2][3]

The time required to identify symptom benefits may take a few weeks or as long as three months. Therefore one should not give up before an adequate trial is completed. In most cases, improved symptoms will be identified within the first month but, if at the end of week 4, one is at the maximum dose of 6 mg per day, in some cases doses as high as 9 mg/day are required for benefit. For those concurrently taking opioids for their chronic pain there may be some risk at higher LDN doses of precipitating mild cases of opioid withdrawal, in which case the LDN dosing should be immediately reduced.

Due to the potential of dosing through a “therapeutic window” while increasing weekly dosing, it may be beneficial to taper back slowly when reaching a maximum dose without achieving any benefit. That benefit may appear with a slow taper of the LDN before discontinuing it.

LDN Dosing regimen:

LDN is taken orally once nightly at bedtime:

• Week 1: 1.5 mg
• Week 2: 3.0 mg
• Week 3: 4.5 mg
• Week 4: 6.0 mg

Side effects are not uncommon, but are generally mild and rarely require discontinuation of the naltrexone. They usually respond to a change in the timing of the dosing or in a reduction of the dose. Side effects may include nausea, headaches, insomnia, or vivid dreams.

• If one develops insomnia, or has vivid or unpleasant dreams, switch to morning dosing.
• If switching to morning doses does not resolve the side effect(s) go back to the previous lower dose.
• If the 1.5 mg dose is not tolerated, a re-trial with 0.5 mg or 1.0 mg dosing may be undertaken.

 

Notes on Dosing

• Despite naltrexone’s short half-life (~6 hours), once-daily dosing is effective for pain relief because the mechanism relies on transient mu-opioid receptor blockade and a subsequent rebound in endogenous opioid tone, not continuous receptor antagonism. Clinical benefit is typically observed after several weeks to up to three months of therapy, reflecting the time needed for neuroadaptive changes and upregulation of endogenous opioids.[1][2][4]

• The most common dose used in research for LDN is 4.5 mg daily, with reduced benefit at higher or lower doses. Dose increases should be delayed if side effects occur, and the maintenance dose is determined by the highest tolerated dose after titration. In recent trials, titration was performed over a 4-week period, with dose escalation based on safety and tolerability, and delayed increments allowed for unacceptable side effects.[1][2]

• There is variability in patient response time and dosing paradigms, and further high-quality trials are needed to standardize LDN protocols and clarify the impact of dosing frequency and titration duration. Most studies and reviews support once-daily dosing, as it aligns with the proposed mechanism and observed clinical efficacy.[1][2][5]

References

1. Naltrexone 6 Mg Once Daily Versus Placebo in Women With Fibromyalgia: A Randomised, Double-Blind, Placebo-Controlled Trial. Due Bruun K, Christensen R, Amris K, et al. The Lancet. Rheumatology. 2024;6(1):e31-e39. doi:10.1016/S2665-9913(23)00278-3.
2. Low-Dose Naltrexone for the Treatment of Fibromyalgia: Investigation of Dose-Response Relationships. Bruun-Plesner K, Blichfeldt-Eckhardt MR, Vaegter HB, et al. Pain Medicine (Malden, Mass.). 2020;21(10):2253-2261. doi:10.1093/pm/pnaa001.
3. Pilot Study of Low-Dose Naltrexone for the Treatment of Chronic Pain Due to Arthritis: A Randomized, Double-Blind, Placebo-Controlled, Crossover Clinical Trial. Beaudette-Zlatanova B, Lew RA, Otis JD, et al. Clinical Therapeutics. 2023;45(5):468-477. doi:10.1016/j.clinthera.2023.03.013.
4. Utility of Naltrexone Treatment for Chronic Inflammatory Dermatologic Conditions: A Systematic Review. Ekelem C, Juhasz M, Khera P, Mesinkovska NA. JAMA Dermatology. 2019;155(2):229-236. doi:10.1001/jamadermatol.2018.4093.
5. Low-Dose Naltrexone’s Utility for Non-Cancer Centralized Pain Conditions: A Scoping Review. Rupp A, Young E, Chadwick AL. Pain Medicine (Malden, Mass.). 2023;24(11):1270-1281. doi:10.1093/pm/pnad074.

Naltrexone for Pain – Overviews

1. 1. Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone
   2. 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.

 

For medical-legal reasons, access to these links is limited to patients enrolled in an Accurate Clinic medical program.

 

Should you wish more information regarding any of the subjects listed – or not listed –  here, please contact Dr. Ehlenberger. He has literally thousands of published articles to share on hundreds of topics associated with pain management, weight loss, nutrition, addiction recovery and emergency medicine. It would take years for you to read them, as it did him.

 

For more information, please contact Accurate Clinic.

 

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