Therapy with low dose naltrexone to improve efficacy of biologic and immune modulatortherapeutic agents

Abstract

The use of low dose naltrexone as an adjuvant therapy to the use of biologic and / or immune modulator therapies is disclosed for the treatment of bowel and gastrointestinal disease, as well as for the treatment of abdominal and joint pain associated therewith.

Description

[0001] Therapy With Low Dose Naltrexone to Improve Efficacy of Biologic and Immune Modulator Therapeutic Agents

[0002] Background of the Invention

[0003] Treatment of Inflammatory Bowel Disease:

[0004] Inflammatory bowel disease (IBD) is a term that encompasses chronic inflammation of the gastrointestinal tract often associated with systemic symptoms. The two major forms of IBD include ulcerative colitis (UC) and Crohn’s disease (CD) The incidence of inflammatory bowel disease is about 10.9 per 100,000 person-years, and there are an estimated 2.39 million Americans with inflammatory bowel diseases which includes 1 in 100 Americans with this condition3The prevalent populations of patients with CD or UC in the United States in 2016 are expected to incur lifetime total costs of $498 billion and $377 billion, respectively, and the price per person increases with age Not only do the costs of treatments and hospitalizations contribute to the economic burden of IBD on the USA but missed productive days from work or school also burden the economy6. Ulcerative colitis and Crohn’s disease are distinguished by the extent and depth of involvement of the GI tract: ulcerative colitis is limited to the mucosal layer of the rectum and colon whereas Crohn’s disease can involve full thickness of the gastrointestinal tract and involve anywhere from the mouth to the anus.

[0005] Treatment of inflammatory bowel disease initially focused on the control of symptoms, but in the past decade GI mucosal healing has become the primary goal of therapy. Treatments have included aminosalicylates (such as mesalamine), immunomodulators (like azathioprine, 6- mercaptopurine, methotrexate), and corticosteroids (such as prednisone, budesonide). The development of anti-TNFa agents has revolutionized the management of IBD. Infliximab, a chimeric monoclonal IgGl antibody against TNF, was the first biologic approved for the treatment of moderate to severe IBD 20 years ago. Early studies showed that infliximab was effective in treating IBD (see Appendix Table 1 for a list of studies)10. However, up to 30% of patients show no clinical benefit after the induction phase [primary nonresponse (PNR)] and up to 50% have to discontinue therapy, either for secondary loss of response (SLR) or a serious adverse event (SAE), such as infusion reaction, infection and malignancy. Both PNR and SLR can be largely explained by low or undetectable concentrations of the drug due to increased nonimmune clearance and / or immunogenicity, or the development of antibodies to infliximab Due to of the development of neutralizing antibodies to the murine component of infliximab that compromised efficacy, adalimumab (ADA or Humira) was developed as a fully human IgGl monoclonal antibody directed against TNFa. Adalimumab was shown to be effective compared to placebo; however, response rates remained less than 50%. Because of the long experience with anti-TNF agents, they are commonly used as the first biologic in clinical practice and most practice guidelines worldwide recommend the use of anti-TNF agents for first line therapy for subjects with Crohn’s disease.

[0006] Unfortunately up to 40% of patients do not respond to TNF inhibitors, and nearly 23-46% of patients experience secondary loss-of-response 1 year after anti-TNF-a treatment leading many to escalation of the dose or shortening of the treatment interval frequency. To improve the efficacy of anti-TNF agents, additional immunosuppressive therapy with immunomodulators drugs have been added to the regimen. Increased risk of serious infection and malignancy has been reported in patients receiving anti-TNF combination therapy when compared with patients receiving anti-TNF monotherapy or immuno-modulator monotherapy. Although the addition of azathioprine to infliximab in subjects with Crohn’s disease15improved the response and decreased the development of neutralizing antibodies, the risk of lymphomas and other malignancies precludes the combinatorial use. The additional of methotrexate to infliximab did not improve response or remission over monotherapy with infliximab in IBD. It is known that combined immunosuppressive therapy increases the risk for lymphoma, cancer and risk of infections.

[0007] Use of anti-TNF agents for arthritis conditions

[0008] In addition to its use in IBD, the United States Food and Drug Administration (FDA) has approved infliximab and adalimumab for active rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and for chronic severe plaque psoriasis in adult patients. Because of the inadequate response rate and development of resistance to anti-TNF agents, other agents have been combined with TNFa agents in an attempt to improve efficacy. The additional of methotrexate to infliximab did not improve response or remission over monotherapy with infliximab in ankylosing spondylitis. Adalimumab has also been shown to be effective in treating arthritis conditions. Unfortunately, when adalimumab is used as a second-line agent after other anti-TNF therapy, the response rate is only about 25% in rheumatoid arthritis. Since anti-TNF agents decrease inflammation, they have also been approved by the FDA for the treatment of arthritis conditions.

[0009] Other biologies developed for treatment of IBD and arthritis

[0010] When anti-TNF agents fail, some patients are changed to other biologic agents including Ustekinumab or Risankizumab (IL-12 / IL-23 antagonists); Vedolizumab (a4 07 integrin antagonist), or more recently Tofacitinib or Upadacitinib (JAK inhibitors), and Ozanimod (SIP receptor modulator). The response rate is also inadequate with some of these newer agents. The clinical response with the JAK inhibitor Tofacitinib was reported in 42.7% and only 20% achieved a clinical remission. Unfortunately, all of the biologies suppress the host immune system and increase the risk for infection, and the risk for reactivation of hepatitis B or tuberculosis. In desperation, many subjects that do not respond to standard of care FDA- approved treatments resort to extreme measures including fecal microbiota transplantation (FMT), surgery, or even stem cell transplants.

[0011] There currently is an unmet need for improved therapy of those with IBD and arthritis without increasing the risk for malignancy, infection and cost. The biologies have improved the rate of mucosal healing or decreased arthritis in those that respond; however only half achieve remission and the response is not durable in a large majority.

[0012] This disclosure incorporates by reference, as if fully set forth herein, United States Patent No. 7,879,870 entitled, “Treatment of Inflammatory and Ulcerative Diseases of the Bowel with Opioid Antagonists”.

[0013] Summary of the invention Anti-TNF agents are approved for use in IBD and arthritis conditions by the FDA.

[0014] Response rates and remission with anti-TNF agents are less than 50%.

[0015] The addition of other immunosuppressant agents to anti-TNF agents increases the risk for lymphoma, cancer, and infections and may not improve efficacy.

[0016] Changing to another biologic agent after the loss of response to a first-line anti-TNF agent provides a lower response rate of about 25%.

[0017] Individuals who are treated with TNF antagonists have a 25 times greater increased risk of reactivating latent infections, especially tuberculosis (TB) and chronic hepatitis B.

[0018] Mechanism of action of low dose naltrexone LDN:

[0019] Naltrexone is a nonselective opioid receptor antagonist at doses of 50 mg or more, but at lower doses (less than 10 mg) given by mouth (orally) once per day (aka “low dose naltrexone” or “LDN”) naltrexone exhibits clinically useful anti-inflammatory activities. Naltrexone is an FDA approved drug and thus the pharmacology (pharmacokinetics and pharmacodynamics) is well known and reported. Naltrexone is approved by the FDA for the treatment of opioid and alcohol abuse syndromes at a dose of 50-100 mg daily27. However, research has shown that at a dose of about 1 / 1 Oth the FDA-approved regimen, naltrexone can exert “paradoxical” analgesic and anti-inflammatory effects.

[0020] The mechanism of action at this low dose is not fully understood. Naltrexone is a nonselective opioid receptor antagonist that interacts with all three classic membrane-bound opioid receptors subtypes: p, 5, and K, and the nuclear OGF receptor. Classic opioid receptors are G-protein-coupled receptors (GPCRs). Likewise, chemokine receptors are also GPCRs and chemokine receptors are responsible for the release of cellular inflammatory cytokines that are small proteins that act as integrators of inflammation Increasing evidence shows that opioids regulate inflammatory responses in part through their effects on cytokines and chemokines and their receptors. Several papers have reported that the heterodimerization between opioid receptors and chemokine receptors can affect their activity. Others have shown that the p opioid receptors cross-talk with chemokine receptors by a mechanism termed heterologous desensitization. It is thought that the desensitization occurs by phosphorylation and internalization of the opioid receptors.

[0021] Toll-like receptors (TLRs) are one of the greatest discoveries of immune science, and have been shown to play an important role in the inflammation response and the Toll-like receptor 4 has been shown to play an important role in neuroinflammation34. It is believed that one potential mechanism of action at the low dose of naltrexone is related to selective blockade of opioid receptors on inflammatory cells peripherally and antagonism on Toll-like receptor 4 (or TLR4). TLR4 are also found on macrophages such as microglia in the central nervous system. Microglia are central nervous system immune cells that are activated by a wide range of triggers. Once activated, microglia produce inflammatory and excitatory factors that can cause pain sensitivity, fatigue, cognitive disruption, sleep disorders, mood disorders, and general malaise. When chronically activated, microglia release proinflammatory cytokines, substance P, nitric oxide, and excitatory amino acids. A decrease in microglial activity by LDN is therefore expected to reverse these pro-inflammatory events and enhance functional status. Cant and colleagues showed that naltrexone inhibited the production of IL-6 secretion by peripheral blood mononuclear cells (PBMC) in vitro following stimulation with ligands for TLR4 and for the intracellular receptors TLR7, TLR8, and TLR9, and naltrexone did not affect cell viability or induce apoptosis of PBMC.

[0022] Brief Description of the Figures

[0023] Fig la. Proposed mechanism of low dose of naltrexone. When a low dose of naltrexone is given, it is hypothesized to block the opioid receptors for only 0-6 hrs. During this time the cells respond by increasing endogenous blood [Met5] -enkephalin or endorphins and receptor number.

[0024] Fig lb. Proposed mechanism of a low dose of naltrexone. After the low dose of naltrexone has been metabolized and excreted, it no longer blocks the opioid receptors and elevated endogenous peptides can now act on the receptors to regulate cell proliferation and inflammation. Fig. 1c. Risks if naltrexone dose is too high. If the naltrexone dose given is too high, then the opioid receptors will remain blocked for longer than 6 hours and up to 24 hrs (at the 50 mg dose) and [Met5]-enkephalin is unable to interact with the receptor to mediate its effect.

[0025] Fig 2. LDN does not decrease the expression of TNFa but reduces the expression of IL-6, IL-12 and Stat3 and Stat4 expression in IBD.

[0026] Fig 3. Disease activity index scores increase in DSS-treated mice (red Column). The activity is significantly decreased with LDN.

[0027] Fig 4. DAI scores in DSS colitis mice showed that there was no improvement in the disease activity index scores with high dose NTX (10 mg / ml).

[0028] Fig 5. Histologic improvement of colitis with naltrexone. Representative H&E sections of distal colon in control and DDS colitis animals are shown above. 5A.) Normal appearance of healthy murine colon (Normal + saline), 5B.) Colon of DSS-treated shows thick mucosa, leukocyte infiltration, and absence of normal crypt architecture. 5C.) Improved architecture and less inflammation are clearly discernable in DSS mice treated with 400 pg / kg naltrexone.

[0029] Fig 6. Mean Crohn’s Disease Activity Index (CD Al) scores ± SEM are shown at baseline (week 0), weeks 4, 8, and 12 after initiation of LDN therapy and 4 weeks after discontinuation of LDN therapy (week 16). **** Significantly different from baseline at p < 0.0001.

[0030] Fig 7. The proportion of subjects achieving the primary study end point with a decline from baseline in CD Al score was significantly greater in those treated with LDN compared to placebo-treated controls (p = 0.009).

[0031] Fig 8. Endoscopic scores after 12 weeks LDN by colonoscopy shows mucosal healing in those on LDN and not placebo. A CDEIS <6 or endoscopic remission was achieved in 44% with Naltrexone and 0% on Placebo.

[0032] Fig 9. Histology inflammation scores significantly improved in those treated with LDN compared to baseline values (p = 0.016) No improvement was noted compared to baseline in placebo-treated patients at 12 weeks. Detailed Description of the Invention

[0033] Much data is consistent that the LDN works via novel anti-inflammatory channels with alternative compelling explanatory models of the mechanism. One prevalent hypothesis states that inducing a small and transient opioid receptor blockade will prompt the body to compensate by upregulating both endogenous opioid peptides and opioid receptors. The opioid receptor upregulation effect of temporary naltrexone blockade has been demonstrated multiple times previously. This “endogenous opioid rebound effect” could have multiple impacts on health and quality of life, including enhanced endogenous analgesia and repression of critical immune factors. This hypothesis regarding the mechanism of action of naltrexone at the low dose is related to its shorter interaction with the opioid receptors (Fig la-c).

[0034] Based upon this hypothesis that low dose naltrexone exerts its effect by transient opioid receptor blockade and subsequent elevation in endogenous enkephalins and endorphins, using a cell culture model system Donahue showed that intermittent treatment with naltrexone, but not continuous therapy, resulted in the same effect as applying enkephalin to the cells. We also showed in a murine model of inflammatory bowel disease that naltrexone only at the lower dose reverse the bowel inflammation whereas the higher dose had no effect.

[0035] As depicted in Fig. 2, LDN does NOT exert its inflammatory effects by decreasing TNFa.

[0036] In a murine model of chemically induced IBD with dextran sulfate sodium (DSS), mice were treated with saline or LDN. Colons were examined at necropsy for the expression of tissue cytokines by a PCR array. TNFa levels were not significantly changed by the LDN treatment (Fig 2A) although histologically and clinically these mice had improvement in colonic inflammation and activity scores (see below). Other cytokines including IL-6 (Fig 2B) and IL-12 (Fig 2C) were decreased with LDN. The mRNA for cytokine signaling intermediates STAT3 and STAT4 were increased in DSS + saline animals (2.20- and 8.03-fold, respectively). These were reduced.

[0037] The tissue levels of TNFa were not statistically different between the groups suggesting that LDN works by a different mechanism that the anti-TNFa biologic agents. LDN reversed other cytokines without eliminating them supporting the evidence that LDN has antiinflammatory properties but not immunosuppressant properties.

[0038] LDN (but not high dose naltrexone) decreases inflammation of disease activity in murine models of IBD:

[0039] Using a chemically-induced mouse model of ulcerative colitis, C57BL / 6J mice (N=64) received either untreated drinking water or water containing 2% dextran sulfate sodium (DSS) to induce ulcerative colitis. After colitis was established (day-3), DSS-treated animals were administered either saline (control), LDN (NTX, 8, or 400 pg / kg) daily or High Dose naltrexone (NTX 10 mg / kg). DSS-treated animals had significantly higher disease activity index (DAI) scores (p<0.001) compared to water controls (Fig 3). Treatment of mice with LDN resulted in significantly lowering the DAI scores is DSS treated mice (Fig 3; P<0.01). In contrast, mice with DSS-induced colitis treated with a high dose (10 mg / kg) of naltrexone had no improvement is the DAI (Figure 4).

[0040] Colons were examined by histology for architecture and inflammation (Fig 5). Fig 5A shows a representative image from the colon of a control mouse that shows normal architecture and no inflammation. Figure 5B shows a representative photo from a mouse treated with DSS with marked thickened mucosa filled with inflammatory cells. Treatment with LDN (Fig 5C) in DSS treated mice improves histologic architecture and decreases inflammation.

[0041] There are 3 classic opioid plasma membrane receptors p (mu), 5 (delta), and K (Kappa) and one nuclear receptor (OGFr). Naltrexone is a nonselective opioid antagonist and decreases activity at all of the receptors. Since delta opioid receptors are the predominant receptor subtype associated with inflammatory cells, the role of the delta receptor inhibition in IBD was tested to determine if the mechanism that LDN decreased inflammation was mediated through the delta opioid receptor. Using both the DSS model for colitis and the 2, 4, 6- trinitrobenzenesulfonic acid (TNBS) model in mice for Crohn’s disease selective 5-receptor antagonists, naltrindole and 7-benzylidenenaltrexone, were administered to examine the role of the 5-opioid receptor in colonic inflammation. Administration of LDN significantly improved overall disease activity indices in this investigation, but the effects were not mediated via the 5-receptor. Clinical studies with LDN in IBD

[0042] Treatment of human adult subjects with Crohn’s disease with low-dose naltrexone.

[0043] In an open-labeled pilot prospective trial, the safety and efficacy of LDN was tested in adults with active Crohn’s disease. Eligible subjects with histologically and endoscopically confirmed active Crohn’s disease activity index (CD Al) score of 220-450 were enrolled in a study using 4.5 mg naltrexone / day. Patients completed quality of life surveys and CD Al scores were assessed pretreatment, every four weeks on therapy and 4-weeks after completion of the study drug. LDN was administered by mouth each evening for a 12-week period. Mean CD Al scores decreased significantly with LDN, and remained lower than baseline 4-weeks after completing therapy (Fig 6). Eighty-nine percent of patients exhibited a response to LDN therapy and 67% achieved a remission (p<0.001). Improvement was recorded in both quality of life surveys with LDN compared to baseline. No laboratory abnormalities were noted.

[0044] LDN therapy for active Crohn’s disease: a placebo-controlled double-blind study in adults.

[0045] In this randomized double-blind controlled study, subjects with active Crohn’s disease (N=40) were randomized to receive either naltrexone (4.5 mg by mouth daily) or placebo for 12 weeks. End points included CD Al scores, endoscopic appearance of mucosa during colonoscopy, histologic inflammatory scores, blood inflammatory markers, and quality of life. Significant improvement was found in those receiving LDN compared to placebo treated controls in CD Al scores (Fig 7) with 88% showing a response by CD Al score and also significant endoscopic mucosal healing (Fig 8). Biopsies were obtained and histology mucosal healing was only found in those on LDN and not placebo (Fig 9). The only statistically significant side effect was that subjects on placebo had significant more fatigue. It was concluded that naltrexone was safe and effective in improving both clinical symptoms of Crohn’s disease and inducing mucosal healing.

[0046] In both of these clinical trials, 60 and 76% of the subjects had previously failed therapy with anti-TNF agents. In spite of prior failure to the anti-TNF biologies, LDN was still very effective in achieving a clinical and histological response. These data would imply that LDN can rescue those that fail or have suboptimal response to anti-TNF agents. In contrast to the low response rate if changed to another biologic (~25%), LDN therapy offers an 88% response rate and 67% remission rate in this population.

[0047] In a 3rd clinical randomized placebo-controlled study in pediatric subjects with Crohn’s disease, LDN was also found to be significant in decreasing disease activity and improving quality of life.

[0048] LDN improves pain.

[0049] The Crohn’s Disease Activity Index score is calculated based upon some objective findings on examination and laboratory tests but also on specific subjective symptoms. A major component of the CD Al score is abdominal pain rated on a scale over the 7-days prior to the visit. Another component of the CD Al score includes the extraintestinal manifestations of arthritis and arthralgias. In the adult Crohn’s clinical trial, treatment with LDN resulted in a significant improvement in overall pain compared to placebo (Fig 10). Note: Subjects with IBD cannot take nonsteroidal anti-inflammatory medications (NSAIDs, like ibuprofen) for their arthritis and join pains because these medications paradoxically increase the inflammation in the gastrointestinal tract and worsen the underlying IBD. An agent that can decrease joint pain without harming the GI tract would be beneficial. These results show that LDN improves overall pain, including joint pain compared to placebo.

[0050] A blood biomarker of inflammation is C-reactive protein (CR-P) which correlates to the IL-6 levels we measured in the mouse colons above (Fig 2B). The C-RP is a nonspecific marker of chronic inflammation and if often monitored in subjects with rheumatoid arthritis to indicate a response to therapy. In the Crohn’s study, C-reactive protein levels decreased from a median value of 2.6 (normal <0.8) at baseline to a value of 0.9 by the 12th week of treatment with LDN, and this change was statistically significant (p = 0.03). Another marker of inflammation, the erythrocyte sedimentation rate (ESR), also responded to LDN treatment. ESR values decreased from a mean baseline value of 23.3 ± 0.4 mm / h to 17.9 ± 0.3 mm / h, (p = 0.04). These studies demonstrate that LDN serves as an anti-inflammatory to decrease pain in the intestine and joints.

[0051] Effects of LDN in treating ulcerative colitis in human subjects: Lie et al (conducted an open-labeled study in subjects with Crohn’s disease (N=28) and ulcerative colitis (N=19) that had not achieved response or clinical remission with FDA- approved standard of care medications. Of the 47 patients, 35 (74.5%) achieved a clinical response. Of those 35 patients, 12 patients had a response of at least 3 months (25.5% of total cohort, 8 CD, 4 UC), whereas a short-lived (between 4 and 12 weeks) improvement was seen in the remaining 23 patients (48.9% of total cohort, 13 CD, 10 UC). There was no statistically significant difference between CD and UC patients in the number of patients that achieved either response or remission (p = 1.000 and p = 0.515 respectively). These data suggest that the response rate to LDN is no different in those with UC compared to CD.

[0052] Safety of LDN

[0053] Naltrexone has been prescribed to patients since 1984 for opiate addiction, and since 1995 for alcohol abuse at a daily dose typically of 50 mg. There is a large safety database of information for both nonclinical and clinical studies that have been conducted with this active pharmaceutical ingredient at doses more than 10 times higher than the proposed maximum LDN dose of 4.5 mg / daily. In the clinical studies using LDN, there have not been any biochemical abnormalities observed in blood chemistries and there is no decrease in immune cell number of function. Recent evidence suggests that rather than suppressing immune function, that low dose of naltrexone may improve immunity while still decreasing inflammation and inducing mucosal healing. Other drugs used to treat inflammatory conditions such as the anti-TNF-a agents can increase the risk for malignancies In contrast, LDN was found to have anticancer properties with inhibition of neuroblastoma and in other cancers.

[0054] Rationale for combination therapy of LDN with anti-TNF agents:

[0055] There is a need for a safe and effective medication to be administered to those treated with anti-TNF agents since not all subjects respond to these biologies. Furthermore, if a response is achieved, it is durable in only 50% or less of the subjects. Addition of another immunomodulating medication like azathioprine to the biologies has been shown to increase the frequency of infections and the risk for cancer and lymphoma. LDN is an opioid receptor antagonist and it may also interact with Toll-like receptors. Our studies show that LDN does not affect TNFa expression. Since the mechanism of action of LDN is unique and is mediated by different pathway / mechanisms than the anti-TNF biologies, it will improve efficacy of these agents without increased toxicity. Response to LDN therapy is rapid with clinical responses within weeks and mucosal response after 12 weeks; therefore a rapid onset of action will be beneficial in subjects with inadequate response to anti-TNF agents.

[0056] One advantage of LDN compared to most biologies, is that LDN is orally bioavailable and does not require parenteral administration. Since LDN is a small molecule rather than a biologic, the cost of manufacturing is markedly reduced.

[0057] Our data provides evidence that LDN and anti-TNFa agents induce a synergistic effect when administered together. The synergistic effect is observed with increased chance of mucosal healing in IBD, longer duration of clinical remission, and improved joint pain. The combination therapy achieves a greater chance in achieving mucosal healing compared to monotherapy with anti-TNFa agents. The combination of LDN to anti-TNFa agents also decreases joint pain more substantially than anti-TNFa agents alone.

[0058] The addition of LDN to anti-TNFa agents does not increase safety risks including risks for infections or cancer.

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[0114] APPENDIX

[0115] Table 1. Data from randomized clinical trial in IBD with infliximab. A. Crohn’s disease and B. Ulcerative colitis. (Papamichael K, Lin S, Moore M, Papaioannou G, Sattler L, Cheifetz AS. Infliximab in inflammatory bowel disease. Ther Adv Chronic Dis. 2019;10:2040622319838443. Published 2019 Mar 26. doi: 10.1177 / 2040622319838443)

Claims

Claims:

1. A method of treating a human subject suffering from inflammatory bowel disease that has not achieved clinical or endoscopic response or remission with biologic therapy or immune modulator therapy, the method comprising administration of low dose naltrexone as an adjuvant treatment.

2. The method of claim 1 wherein the dose of naltrexone is less than about lOmg / day by mouth.

3. The method of claim 2 wherein the biologic therapy is one or more biologies selected from among the group comprising anti-TNFa biologies, IL-12 / IL-23 antagonists, a4 07 integrin antagonists, JAK inhibitors, and SIP receptor modulators.

4. The method of claim 2 wherein the biologic therapy is one or more biologies selected from among the group comprising Infliximab, Adalimumab, Golimumab, Certolizumab, Ustekinumab Risankizumab, Vedolizumab, Tofacitinib, Upadacitinib, and Ozanimod.

5. The method of claim 2 wherein the immunomodulating agent is selected from among the group comprising aminosalicylates, azathioprine, 6-mercaptopurine, methotrexate, prednisone, and budesonide.

6. The method of claim 2 wherein the subject suffers from frequent bowel movements wherein the frequency of bowel movements is reduced after treatment.

7. A method of treating a human subject suffering from pain that has not achieved clinical response with biologic therapy or immune modulator therapy, the method comprising administration of low dose naltrexone as an adjuvant treatment.

8. The method of claim 7 wherein the pain is joint pain.

9. The method of claim 7 wherein the pain is abdominal pain.

10. A combination of low dose naltrexone and one or more biologic or immune modulator agents for use in the treatment of diseases of the gastrointestinal tract.

11. The combination of claim 10 wherein naltrexone is administered at dosage levels at or below lOmg per day.