Low-Dose Naltrexone Treatment of Hashimoto’s Thyroiditis

Abstract

Chronic lymphocytic thyroiditis, also known as Hashimoto’s thyroiditis, is the most common cause of spontaneously occurring hypothyroidism in adults in the United States. Treatment for this condition is thyroid hormone replacement once hypothyroidism develops since there is no known effective treatment to halt the underlying thyroiditis that eventually destroys the thyroid gland. Selenium supplements have been reported to reduce anti-thyroid antibody titers significantly but not to prevent the eventual development of hypothyroidism. Low-dose naltrexone (LDN) has been promoted in books and on Internet websites as an effective treatment to reduce thyroid inflammation and symptoms in patients with this condition. However, there is no published scientific data to substantiate these claims.

Full text

317© Springer Nature Switzerland AG 2019
M. T. McDermott (ed.), Management of Patients
with Pseudo- Endocrine Disorders,
https://doi.org/10.1007/978-3-030-22720-3_24
Chapter 24
Low-Dose Naltrexone
Treatment ofHashimoto’s
Thyroiditis
MichaelT.McDermott
A 51-year-old man came to the office to establish care with an
endocrinologist. He just moved to this community from out
of state. He was diagnosed years ago with hypothyroidism
and low testosterone; he doesn’t recall the tests that were
done to establish these diagnoses. He currently takes levothy-
roxine 225 mcg daily, liothyronine 5 mcg BID and Depo-
testosterone 100mg every week. He feels generally well but
has chronic anxiety and trouble sleeping. He has some fatigue
but says that his current medication regimen helps consider-
ably. His previous doctor told him that his TSH, which is usu-
ally low, is not an accurate measure of his thyroid status since
he has severe fatigue when his TSH is normal. He was told
that his treatment goal should be to keep his free T4 and free
T3 levels within the normal range but that his symptoms are
the most reliable indicator of the adequacy of his thyroid
hormone therapy. He has done extensive Internet research
that has confirmed that, as his previous doctor told him, the
M. T. McDermott (*)
University of Colorado Hospital, Aurora, CO, USA
e-mail: michael.mcdermott@cuanschutz.edu
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318
TSH is not a good test for him. A previous MRI of his pitu-
itary gland was normal. He also read information during his
research that Hashimoto’s thyroiditis may be improved or
cured with low-dose extended-release compounded naltrex-
one therapy. He requests that a prescription for low-dose
naltrexone be sent to his local compounding pharmacy that
has told him they will compound it for him if he has a pre-
scription from a physician. His most recent labs are as fol-
lows: TSH 0.01mU/L, free T4 1.8ng/dl, and free T3 2.4pg/ml.
Discussion
Hashimoto’s thyroiditis (chronic lymphocytic thyroiditis) is
the most common etiology of primary hypothyroidism in
adults in the United States. Hashimoto’s thyroiditis is a
genetically based chronic inflammatory condition that leads
to gradual but progressive destruction of the thyroid gland,
rendering it unable to make sufficient amounts of thyroid
hormone to meet the needs of peripheral tissues [1].
Hashimoto’ s thyroiditis is the most common of all autoim-
mune diseases. While a genetic predisposition plays a domi-
nant role in its development, environmental factors may also
have an important influence. Nutritional factors, for example,
have been linked to a higher risk for developing Hashimoto’
s thyroiditis; these include iodine excess, selenium deficiency,
and possibly deficiencies of iron and vitamin D [2].
Interestingly, selenium supplementation has been shown to
reduce thyroid autoantibody titers in patients with
Hashimoto’s thyroiditis; however, there is no evidence that
selenium reverses or prevents progression of their thyroid
dysfunction [3].
The diagnosis of Hashimoto’s thyroiditis is made by dem-
onstrating elevated levels of anti-thyroid peroxidase anti-
bodies (anti-TPO) and/or anti-thyroglobulin antibodies
(anti-Tg) in the circulation. However, measurement of these
anti- thyroid antibodies in hypothyroid subjects is a contro-
versial topic. Routine antibody measurement is not recom-
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319
mended in the current clinical practice guidelines of the
American Association of Clinical Endocrinologists (AACE)
and the American Thyroid Association (ATA) [4] because
adults with hypothyroidism not due to iatrogenic causes
(surgery, radioiodine ablation) or medications nearly always
have Hashimoto’s thyroiditis; therefore, thyroid autoanti-
body testing offers little additional information and does
not usually affect treatment decisions. However, some pro-
viders find it beneficial to demonstrate to their patients that
their hypothyroidism has an autoimmune etiology; this may
also facilitate a discussion about the increased risk of devel-
oping other autoimmune disorders for which increased vigi-
lance may be useful. Thyroid sonography is not generally
indicated in the evaluation of hypothyroidism unless thy-
roid nodules are palpable on physical examination or have
been identified incidentally by other imaging studies; when
performed it often shows a hypoechogenic pattern in the
thyroid parenchyma in patients with chronic lymphocytic
thyroiditis [1].
The treatment of Hashimoto’s thyroiditis is thyroid hor-
mone replacement once hypothyroidism develops as a
result of the chronic lymphocytic inflammation.
Levothyroxine (LT4) is the recommended replacement
medication and should be given in doses sufficient to main-
tain the serum TSH level within the reference range [4, 5].
The majority of affected patients will have relief or resolu-
tion of their symptoms with this therapy. However, as dis-
cussed in the previous chapter, some patients may continue
to experience symptoms consistent with thyroid hormone
deficiency despite adequate LT4 replacement therapy [6–
14]. Some providers may then choose a trial of combination
LT4 plus liothyronine (LT3) in roughly a 10:1T4 to T3 ratio
or porcine desiccated thyroid extract (DTE), which has
approximately a 4:1T4 to T3 ratio. Neither of these are con-
sidered first-line therapy, but the ATA and AACE guideline
authors concede that while there is no evidence for superi-
ority of these combined T4/T3 regimens on symptoms or
other outcomes and there is no long- term safety data, it is
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reasonable to consider a trial of combined therapy in
patients who continue to suffer symptoms despite adequate
LT4 therapy (see more complete discussion of this issue in
the previous chapter) [4, 5].
Nonetheless, the ATA survey (discussed in the previous
chapter) of 12,000 hypothyroid patients that showed wide-
spread dissatisfaction with their thyroid hormone replace-
ment therapy [13] consisted of 60% who were taking LT4
alone, 25% who were taking combination LT4/LT3, and
10% who were taking DTE or a compounded thyroid hor-
mone preparation. Therefore, even the available combina-
tion T4/T3 regimens do not resolve all symptoms in some
patients.
Blogs fromaHashimoto’s Disease Website
(Unedited)
• I am currently going through this now. I feel like crap, no
energy depressed moody dizzy ect. My labs have been in
range and my Endo doctor says my symptoms are not
related to Hashimoto because my thyroid test are in range.
But they cant find any other issues so now they are just
treating me like I am crazy and a Hypochonchiac when I
tell them what I’m experiencing.
• This is exactly what thyroid patients go through, doctors
dismissing our symptoms when labs are in-range. They
do not realize they are relying on outdated lab values or
that the difference between in-range and optimal can
make a dramatic improvement in our quality of life.
And yet we continue to be ignored by a majority of
endocrinologists and thyroid specialists. Seven out of
eight thyroid patients are women. Is it any wonder we
are ignored?
• Yes it is BS but what’s even worse is being sick for 30years
and them telling you you’re fine when you know you
aren’t. Then you are finally diagnosed and they tell you
well this isn’t something traditional medicine treats its
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more of a holistic health thing. Are you serious!!! I do feel
better now on Armour and healthy diet than I ever did on
Synthroid so that’s a plus.
• Endocrinologists are trained but not educated.
A Cure forHashimoto’s Thyroiditis Is Not
Currently Available
The most commonly cited explanation for persistent symp-
toms in hypothyroid patients who are treated with LT4 or T4/
T3 combinations and have serum TSH levels within the refer-
ence range or even within the “optimal range” of 0.45–
2.0mU/L is that the symptoms may not be thyroid-related or
endocrine-related at all [15]. However, data from one study
suggested that chronic lymphocytic thyroiditis may possibly
cause symptoms that are independent of and not related to
thyroid hormone levels [16]. Furthermore, multiple other
autoimmune conditions are known to occur more commonly
in patients with chronic lymphocytic thyroiditis [17, 18], add-
ing to the complexity of symptom management. So, the
important question arises: is it possible that Hashimoto’s
thyroiditis itself could be cured before there is extensive thy-
roid inflammation and gland destruction?
Autoimmune diseases that destroy some organ systems
(joints, kidneys, liver, central nervous system, eyes, skin) are
often treated with aggressive immunosuppressive therapies
because relatively simple replacement therapies for these
organ systems are not available. Due to the frequent side
effects and significant toxicities of immunosuppressive agents,
they have not been well studied and are not indicated in
patients with Hashimoto’s thyroiditis. Instead, affected
patients are generally monitored until they develop mild
hypothyroidism, at which point thyroid hormone replace-
ment therapy is initiated.
Therefore, there is interest in finding therapies that are
more benign than currently available immunosuppressive
agents and that could potentially be used to reduce or abolish
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the thyroid inflammation to prevent further thyroid destruc-
tion or possibly even allow thyroid regeneration. For exam-
ple, as mentioned above, selenium supplementation has been
shown to reduce thyroid autoantibody titers in patients with
this condition; disappointingly, however, there is no evidence
that selenium can reverse or prevent progression of thyroid
dysfunction [3]. So here is where the murky origins of low-
dose naltrexone as a treatment for Hashimoto’s thyroiditis
begin.
Background onLow-Dose Naltrexone
Endogenous opioids and opioid antagonists are proposed to
play a role in healing and repair of tissues. This has led to the
use of low-dose naltrexone (LDN) as a possible treatment for
numerous disorders [20]. Dr. Bernard Bihari, “a LDN pioneer
and champion” is featured in a 2002 online video describing
his work with LDN; an online tribute credits him with
improving the lives and relieving symptoms in “tens of thou-
sands (some say hundreds of thousands) of people with mul-
tiple sclerosis, rheumatoid arthritis, lupus, HIV/AIDS, and
even cancer” [19]. In her book Honest Medicine, Julia
Schopick proposes LDN as an “effective, time-tested, inex-
pensive treatment for life-threatening diseases” to include
“multiple sclerosis, epilepsy, liver disease, lupus, rheumatoid
arthritis, and other disorders” [20].
Scientific Evidence forLow-Dose Naltrexone
Is there credible science to support these claims? In a 2007
study published in the American Journal of Gastroenterology,
Dr. Jill Smith did report significant improvements in the
Crohn’s Disease Activity Index during 12weeks of treatment
with LDN and for 4weeks after discontinuation of the medi-
cation in patients with active Crohn’s disease [21]. Other
studies followed with mixed results. Subsequently, a 2018
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Cochrane Database Systematic Review of this issue con-
cluded that there is “insufficient evidence to allow any firm
conclusions regarding the efficacy and safety of LDN for
patients with active Crohn’s disease” [22].
I have searched all credible sources and have found no
published evidence that LDN is beneficial in patients with
thyroid or other endocrine disorders, autoimmune or other-
wise. As devoted and well-educated clinician scientists and
experts in the field, we should always be seeking innovative
approaches to evaluation and treatment of our patients who
are suffering from endocrine diseases and pseudo-endocrine
disorders since our primary goal is to relieve suffering and
improve our patients’ quality of life. Our evaluation and man-
agement recommendations must, in my opinion, be individu-
alized and innovative but should also be evidence-based to
ensure that the safety and welfare of our patients is foremost
in our plans.
What Is theBest Way toManage this Patient’s
Symptoms andConcerns andtoPractice
Good Medicine?
It is critically important to educate patients regarding medi-
cal information they find on the Internet. This has been well
covered in other chapters, so I will briefly say only that
patients should be informed that both good information and
unreliable and unsubstantiated information can be found on
the Internet. One must be careful to determine the source of
the information given in order to evaluate its credibility. In
this case, some Internet sites make claims of significant ben-
eficial effects of LDN but without solid scientific evidence to
substantiate these claims. A review of the existing scientific
literature does show some initial reports of benefit in patients
with Crohn’s disease, but a large Cochrane systemic review of
all existing studies did not find evidence for benefit. LDN has
not been studied in patients with Hashimoto’s thyroiditis.
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This information is worth discussing with the patient.
Doing so indicates that you acknowledge that he/she is
seeking relief of symptoms that are adversely affecting his/
her quality of life and respects his/her initiative for investi-
gating measures that might be taken to improve quality of
life. At the same time, it emphasizes that you, as the physi-
cian, practice evidence-based medicine and do not believe
that the use of unproven therapies is good medical
practice.
However, because this patient has sought out your opinion
and entrusted his healthcare to you, it is incumbent upon the
provider to show him respect and compassion. Listening care-
fully, examining him, offering to order additional testing, if
appropriate, and discussing alternative explanations for his
symptoms and management options that emphasize healthy
lifestyle measures and treatment with evidence-based thera-
pies, if they are available, are always appropriate and can go a
long way toward symptom resolution and good quality of life.
References
1. Chaker L, Bianco AC, Jonklass J, Peeters RP. Hypothyroidism.
Lancet. 2017;390(10101):1550–62.
2. Hu S, Rayman MP. Multiple nutritional factors and the risk of
Hashimoto’s thyroiditis. Thyroid. 2017;27(5):597–610.
3. Wichman J, Winther KH, Bonnema SJ, Hegedus L. Selenium
supplementation significantly reduces thyroid autoantibody lev-
els in patients with chronic autoimmune thyroiditis: a systematic
review and meta-analysis. Thyroid. 2016;26(12):1681–92.
4. Garber J, etal. Clinical practice guidelines for hypothyroidism
in adults: cosponsored by the American Association of Clinical
Endocrinologists and the American Thyroid Association.
Endocr Pract. 2012;18(6):988–1028. And Thyroid 2012
Dec;22(12):1200–35.
5. Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR,
Celi FS, Cooper DS, American Thyroid Association Task Force
on Thyroid Hormone Replacement, et al. Guidelines for the
treatment of hypothyroidism: prepared by the American Thyroid
M. T. McDermott
michael.mcdermott@cuanschutz.edu

325
Association Task Force on thyroid hormone replacement.
Thyroid. 2014;24(12):1670–751.
6. Thvilum M, Brandt F, Almind D, Christensen K, Brix TH,
Hegedüs L. Increased psychiatric morbidity before and after
the diagnosis of hypothyroidism: a nationwide register study.
Thyroid. 2014;24(5):802–8.
7. Quinque EM, Villinger A, Kratzsch J, Karger S.Patient-reported
outcomes in adequately treated hypothyroidism– insights from
the German versions of ThyQoL, ThySRQ and ThyTSQ.Health
Qual Life Outcomes. 2013;11:68.
8. Samuels MH, Kolobova I, Smeraglio A, Peters D, Janowsky JS,
Schuff KG. The effects of levothyroxine replacement or sup-
pressive therapy on health status, mood, and cognition. J Clin
Endocrinol Metab. 2014;99(3):843–51.
9. Samuels MH, Kolobova I, Smeraglio A, Niederhausen M,
Janowsky JS, Schuff KG. Effect of thyroid function varia-
tions within the laboratory reference range on health status,
mood, and cognition in levothyroxine-treated subjects. Thyroid.
2016;26(9):1173–84.
10. Santoro N, Braunstein GD, Butts CL, Martin KA, McDermott
M, Pinkerton JV.Compounded bioidentical hormones in endo-
crinology practice: an Endocrine Society scientific statement. J
Clin Endocrinol Metab. 2016;101(4):1318–43.
11. Biondi B, Wartofsky L.Treatment with thyroid hormone. Endocr
Rev. 2014;35(3):433–512.
12. Winther KH, Cramon P, Watt T, Bjorner JB, Ekholm O, Feldt-
Rasmussen U, Groenvold M, et al. Disease-specific as well as
generic quality of life is widely impacted in autoimmune hypo-
thyroidism and improves during the first six months of levothy-
roxine therapy. PLoS One. 2016;11(6):e0156925.
13. Peterson SJ, Cappola AR, Castro MR, etal. Degrees of satis-
faction and coexistent diseases in those responding to a sur-
vey exploring perceptions about treatment of hypothyroidism.
Thyroid. 2018;28(6):707–21.
14. McAninch EA, Bianco AC.The history and future treatment of
hypothyroidism. Ann Intern Med. 2016;164(1):50–6.
15. Guglielmi R, Frasoldati A, Zini M, Grimaldi F, Gharib H,
Garber JR, Papini E. Italian Association of Clinical
Endocrinologists Statement-Replacement Therapy for Primary
Hypothyroidism: a brief guide for clinical practice. Endocr
Pract. 2016;22(11):1319–26.
Chapter 24. Low-Dose Naltrexone Treatment…
michael.mcdermott@cuanschutz.edu

326
16. Ott J, Promberger R, Kober F, Neuhold N, Tea M, Huber JC,
Hermann M.Hashimoto’ s thyroiditis affects symptom load and
quality of life unrelated to hypothyroidism: a prospective case-
control study in women undergoing thyroidectomy for benign
goiter. Thyroid. 2011;21(2):161–7.
17. Boelaert K, Newby PR, Simmonds MJ, Holder RL, Carr-Smith
JD, Heward JM, Manji N, et al. Prevalence and relative risk of
other autoimmune diseases in subjects with autoimmune thyroid
disease. Am J Med. 2010;123(2):183.e1–9.
18. Roy A, Laszkowska M, Sundstrom J, Lebwohl B, Green PH,
Kämpe O, Ludvigsson JF.Prevalence of celiac disease in patients
with autoimmune thyroid disease: a meta-analysis. Thyroid.
2016;26(7):880–90.
19. http://www.lowdosenaltrexone.org.
20. Schopick, Julia E and Berkson Burton M. Honest Medicine.
2011.
21. Smith J.Low dose naltrexone therapy improves active Crohn’s
disease. Am J Gastroenterol. 2007;102:820–8.
22. Parker CE.Low dose naltrexone for induction of remission in
Crohn’s disease. Cochrane Database Syst Rev. 2018;4:CD010410.
https://doi.org/10.1002/14651858.CD010410.pub3.
M. T. McDermott
michael.mcdermott@cuanschutz.edu