In tiny doses, an addiction medication eases chronic pain

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A growing group of chronic pain patients are turning to the addiction treatment medication naltrexone, which can substantially relieve pain when used in micro-doses, writes Alex Smith for National Public Radio.

Lori Pinkley, a 50-year-old from Kansas City, has struggled with puzzling chronic pain since she was 15. She's had endless disappointing visits with doctors. Some said they couldn't help her. Others diagnosed her with everything from fibromyalgia to lipedema to the rare Ehlers-Danlos syndrome.

Pinkley has taken opioids a few times after surgeries but says they never helped her underlying pain. "I hate opioids with a passion," Pinkley says. "An absolute passion."

Recently, she joined a growing group of patients using an outside-the-box remedy: naltrexone. It is usually used to treat addiction, in a pill form for alcohol and as a pill or a monthly shot for opioids, reports NPR in a 23 September article.

As the medical establishment tries to do a huge u-turn after two disastrous decades of pushing long-term opioid use for chronic pain, scientists have been struggling to develop safe, effective alternatives.

When naltrexone is used to treat addiction in pill form, it's prescribed at 50 mg, but chronic-pain patients say it helps their pain at doses of less than a tenth of that.

Click here for the report on NPR.

Low-dose naltrexone has lurked for years on the fringes of medicine, but its zealous advocates worry that it may be stuck there. Naltrexone, which can be produced generically, is not even manufactured at the low doses that seem to be best for pain patients.

Instead, patients go to compounding pharmacies or resort to DIY methods – YouTube videos and online support groups show people how to turn 50 mg pills into a low liquid dose.

Some doctors prescribe it off-label even though it's not FDA-approved for pain.

University of Kansas pain specialist Dr Andrea Nicol recently started prescribing it to her patients, including Pinkley. Nicol explains that for addiction patients, it works by blocking opioid receptors – some of the brain's most important feel-good regions. So it prevents patients from feeling high and can help patients resist cravings.

At low doses of about 4.5 mgs, however, naltrexone seems to work completely differently.

"What it's felt to do is not shut down the system, but restore some balance to the opioid system," Nicol says.

Click here for the report on NPR.

Some of the hype over low-dose naltrexone has included some pretty extreme claims with limited research to back them, like using it to treat multiple sclerosis and neuropathic pain or even using it as a weight-loss drug.

In the past two years, however, there's been a big increase in new studies published on low-dose naltrexone, many strengthening its claims as a treatment for chronic pain, though most of these were still small pilot studies.

Dr Bruce Vrooman, an associate professor at Dartmouth's Geisel School of Medicine, was an author of a recent review of low-dose naltrexone research. Vrooman says that when it comes to treating some patients with complex chronic pain, low-dose naltrexone appears to be more effective and well-tolerated than the big-name opioids that dominated pain management for decades.

"Those patients may report that this is indeed a game changer," Vrooman says. "It may truly help them with their activities, help them feel better."

Click here for the report on NPR.

So how does it work? Scientists think that for many chronic pain patients, the central nervous system gets overworked and agitated. Pain signals fire in an out-of-control feedback loop that drowns out the body's natural pain-relieving systems.

They suspect that low doses of naltrexone dampen that inflammation and kick-start the body's production of pain-killing endorphins – all with relatively minor side effects.

Despite the promise of low-dose naltrexone, its advocates say few doctors know about it.

The low-dose version is generally not covered by insurance, so patients typically have to pay out of pocket to have it specially made at compounding pharmacies.

Click here for the report on NPR.

Advocates worry that the treatment is doomed to be stuck on the periphery of medicine because, as a 50-year-old drug, naltrexone can be made generically.

Patricia Danzon, a professor of health care management at the Wharton School at the University of Pennsylvania, explains that drug companies don't have much interest in producing a new drug unless they can be the only maker of it.

"Bringing a new drug to market requires getting FDA approval and that requires doing clinical trials," Danzon says. "That's a significant investment, and companies – unsurprisingly – are not willing to do that unless they can get a patent and be the sole supplier of that drug for at least some period of time."

And without a drug company's backing, a treatment like low-dose naltrexone is unlikely to get the big promotional push out to doctors and TV advertisements that have turned drugs like Humira or Chantix into household names.

"It's absolutely true that once a product becomes generic, you don't see promotion happening, because it never pays a generic company to promote something if there are multiple versions of it available and they can't be sure that they'll capture the reward on that promotion," Danzon says.

Click here for the report on NPR.

The drugmaker Alkermes has had huge success with its exclusive rights to the extended-release version of naltrexone, called Vivitrol. In a statement for this story, the company says it hasn't seen enough evidence to support the use of low-dose naltrexone to treat chronic pain and therefore is remaining focused on opioid addiction treatment.

Pinkley says she is frustrated that there are so many missing pieces in the puzzle of understanding and treating chronic pain, but she, too, has become a believer in naltrexone.

She has been taking it for about a year now, at first paying $50 a month out of pocket to have the prescription filled at a compounding pharmacy. In July, her insurance started covering it.

"I can go from having days that I really don't want to get out of bed because I hurt so bad," she says, "to within a half-hour of taking it, I'm up and running, moving around, on the computer, able to do stuff."

* This story is part of NPR's reporting project with KCUR and Kaiser Health News.

Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes

American Journal of Hospice and Palliative Medicine

Abstract

Pain can have a devastating effect on the quality of life of patients in palliative medicine. Thus far, majority of research has been centered on opioid-based pain management, with a limited empirical evidence for the use of nonopioid medications in palliative care. However, opioid and nonopioid medications such as nonsteroidal anti-inflammatory drugs have their limitations in the clinical use due to risk of adverse effects, therefore, there is a need for more research to be directed to finding an alternative approach to pain management in comfort care setting. 

The purpose of this article is to discuss a potential new drug that would adequately alleviate pain and enhance quality of life without significant risks of adverse effects that would limit its use. 

Naltrexone is a reversible competitive antagonist at μ-opioid and κ-opioid receptors, which when used at standard doses of 50 to 150 mg was initially intended for use in opioid and alcohol use disorders. However, it was discovered that its use in low doses follows alternate pharmacodynamic pathways with various effects. When used in doses of 1 to 5 mg it acts as a glial modulator with a neuroprotective effect via inhibition of microglial activation. 

It binds to Toll-like receptor 4 and acts as an antagonist, therefore inhibiting the downstream cellular signaling pathways that ultimately lead to pro-inflammatory cytokines, therefore reducing inflammatory response. Its other mode of action involves transient opioid receptor blockade ensuing from low-dose use which upregulates opioid signaling resulting in increased levels of endogenous opioid production, known as opioid rebound effect. 

Low dose naltrexone has gained popularity as an off-label treatment of several autoimmune diseases including multiple sclerosis and inflammatory bowel disease, as well as chronic pain disorders including fibromyalgia, complex regional pain syndrome, and diabetic neuropathy. Low-dose naltrexone (LDN) may also have utility in improving mood disorders and the potential to enhance the quality of life. This article will therefore propose the potential off-label use of LDN in management of nonmalignant pain in the palliative medicine setting.

Authors

Diana Trofimovitch and Steven J Baumrucker

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization.

Medical Sciences

Abstract

Naltrexone and naloxone are classical opioid antagonists. In substantially lower than standard doses, they exert different pharmacodynamics. Low-dose naltrexone (LDN), considered in a daily dose of 1 to 5 mg, has been shown to reduce glial inflammatory response by modulating Toll-like receptor 4 signaling in addition to systemically upregulating endogenous opioid signaling by transient opioid-receptor blockade. Clinical reports of LDN have demonstrated possible benefits in diseases such as fibromyalgia, Crohn's disease, multiple sclerosis, complex-regional pain syndrome, Hailey-Hailey disease, and cancer. 

In a dosing range at less than 1 μg per day, oral naltrexone or intravenous naloxone potentiate opioid analgesia by acting on filamin A, a scaffolding protein involved in μ-opioid receptor signaling. This dose is termed ultra low-dose naltrexone/naloxone (ULDN). It has been of use in postoperative control of analgesia by reducing the need for the total amount of opioids following surgery, as well as ameliorating certain side-effects of opioid-related treatment. 

A dosing range between 1 μg and 1 mg comprises very low-dose naltrexone (VLDN), which has primarily been used as an experimental adjunct treatment for boosting tolerability of opioid-weaning methadone taper. In general, all of the low-dose features regarding naltrexone and naloxone have been only recently and still scarcely scientifically evaluated. 

This review aims to present an overview of the current knowledge on these topics and summarize the key findings published in peer-review sources. The existing potential of LDN, VLDN, and ULDN for various areas of biomedicine has still not been thoroughly and comprehensively addressed.

Authors

K Toljan and B Vrooman. Toljan is in the Department of Pathophysiology, University of Zagreb School of Medicine. B Vrooman is in the Department of Anesthesiology at Dartmouth-Hitchcock Medical Center and the Geisel School of Medicine at Dartmouth, US.

In Tiny Doses, An Addiction Medication Moonlights As A Treatment For Chronic Pain

Pharmacology Update: Low-Dose Naltrexone as a Possible Nonopioid Modality for Some Chronic, Nonmalignant Pain Syndromes

Low-Dose Naltrexone (LDN)-Review of Therapeutic Utilization.


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