

Today’s post is from SBP contributor Avicenna. Here’s his bio and his prior posts.

An estimated 2 to 3% of the developed world – roughly 1 million Canadians and 10 million Americans – suffer from a debilitating form of chronic pain, called neuropathic pain (NP) or neuralgia.(1,2) What’s worse is that these numbers are expected to rise because of an aging population and the subsequent increase in diabetes and shingles, two common diseases associated with NP.(3,4) More simply called nerve pain, NP is quite a challenging medical condition to treat since current treatment options provide only modest relief, and usually with problematic side effects.

I’ve recently had a few patients asking me about a new over-the-counter treatment for NP. The product is called Neuragen which is a homeopathic mixture in a solution of five essential oil extracts.(5,6) Neuragen comes in either a “concentrated” dropper-bottle (5 mL or 15 mL ) or an 8 gram gel jar. Canada-based Origin Biomed, Neuragen’s manufacturer, boasts of impressive pain relief with Neuragen, including “Effective for up to 8 Hours”, “Effective for more than 80% of sufferers”, and “Highly effective for 63% of sufferers”. Before looking at the evidence for Neuragen, let’s look at what we’re trying to treat: a condition called neuropathic pain.

Pain Overview

Pain may be described as either nociceptive or neuropathic. Nociceptive pain is a reaction to painful stimuli, such as cutting of the skin or breaking of a bone, that results in the activation of nerve endings in the inner organs (i.e., viscera) or from skin, muscle or bone (somatic). Visceral pain typically presents itself as a dull, gnawing, cramping, aching or sharp pain, while somatic pain is more often described as aching, throbbing, stabbing, pressure pain. Nociceptive paint is useful, helping us avoid harm (that surface is hot!), or alerting us that something is wrong (I think I have a kidney stone!).(8)

The mechanism by which we perceive nociceptive pain is fairly well understood. Signalling is initiated by activation of peripheral nerves by inflammation mediators. These fire pain signals to a second nerve cell in the spine’s grey matter (yes, the spine has grey matter!). This second nerve cell then relays the pain signals into the brain centers for processing. How the brain perceives this signal to cause the sensation of pain is called pain modulation, and is less well understood. Example of modulation which may drive the placebo effect include the brain’s reward system or expectation of reward.

Compared to nociceptive pain, neuropathic pain (NP) is abnormal and serves no useful purpose. NP is usually described as burning and tingling, “pins and needles”, or even an “electric shock”-like feeling. Other descriptions include: cutting, prickling, throbbing, crushing, shooting, stabbing, lancinating, or jabbing. NP can have have different triggers including a very light touch, or cold or cool temperatures.(8,9) The pain can be continuous or spontaneous.

Neuropathic brain is caused by lesions in pain sensation pathways in the central (i.e., brain, spine) or peripheral (e.g., nerves in skin, inner organs) nervous system. Neuropathic pain has several causes which can include: trauma/surgery, compression or entrapment of nerves (e.g. sciatica), endocrine disorders such as diabetes, and infections such as herpes zoster or HIV.(7) While some causes can be well understood, others require evaluations by neurologists and pain specialists.

A combination of mechanisms contribute to the perception of neuropathic pain. First, when intense, prolonged or repeated stimuli are applied to damaged or inflammed skin, the threshold to trigger a pain signal by nerves is lowered and this causes a higher frequency of pain signal to be sent to the spine and brain. Inflammation mediators (e.g., prostaglandins, leukotriene) contribute to this sensitization process. In neuropathic pain, this sensitization sometimes triggers pain without stimuli and is thought to be partly caused by increased sodium channels of nerve cells. Also, damaged nerve cells may be more sensitive to norepinephrine.(9) To worsen the situation, NP can co-exist with a similar disease called neuropathy, which is the loss of feeling and touch in an affected area – this condition is common in diabetics, who lose sensation in their extremities.

Evidence Based Treatments of Neuropathic Pain

Because NP can be unrelenting and severe, it’s often accompanied by anxiety, sleep problems and even depression. While pain is the primary symptom we treat, only partial control is probably realistic, based on existing treatment options. A treatment is generally considered effective if it reduces pain by about a half, by measures such as the 10-point visual analogue score (VAS) or verbal rating scale (VRS). Frequently, pain is also measured by use of various global impression of pain questionnaire (GIPQ), or the McGill Pain Questionnaire (MPQ). Effective therapies need to reduce pain for extended periods.

Drug treatments are the primary approach for NP. When we sort the best options as best we can, it turns out a group of antidepressants called tricyclics, and a couple of epilepsy drugs are the most treatment options. The newer antidepressants comes in second, and narcotics like morphine come in third choice because of their side effects profile and addictive properties.(1,8)

These numbers illustrate the effectiveness of current treatment options: For every 3 patients treated, 1 will have effective pain relief if they’re treated with a tricyclic or the antidepressant Effexor, compared to placebo. Of these patients, one in 16 patient taking a tricyclic and 1 in 28 patient taking Effexor may have an intolerable side effect. The newer anticonvulsant Lyrica fares almost as good in term of efficacy, but side effects are more common. The epilepsy drug Neurontin is as effective as Lyrica, and may be better tolerated (10, 11, 12). To evaluate these therapies, most trials lasted from two months to a year or more. (Remember this point, we’ll come back to it). Trials generally used weekly or monthly pain measurements to evaluate efficacy. The bottom line for NP treatments is that we have a few alternatives, all with some efficacy, but nothing works really well. And the tolerability can vary.

What is Neuragen and How Might it Work?

In the 1800’s, a time before germ theory, the discovery of insulin, surgical anesthesia or sterile technique, German physician Samuel Hahnemann invented the rules for a practice he called homeopathy. From the Skeptic’s dictionary:

Classical homeopathy is generally defined as a system of medical treatment based on the use of minute quantities of remedies that in larger doses produce effects similar to those of the disease being treated. Hahnemann believed that very small doses of a medication could have very powerful healing effects because their potency could be affected by vigorous and methodical shaking (succussion). Hahnemann referred to this alleged increase in potency by vigorous shaking as dynamization. Hahnemann thought succussion could release “immaterial and spiritual powers,” thereby making substances more active. “Tapping on a leather pad or the heel of the hand was alleged to double the dilution”.

Homeopathy has never been shown to reliably produce any effects other than placebo responses. And how could it? Homeopathic remedies are normally diluted so significantly, there’s actually no active ingredients present. And there’s no evidence to suggest that water can “remember” what’s been diluted in it.

The homeopathic ingredients in Neuragen include St. John’s Wort (Hypericum perforatum), wolfbane (Aconitum Napellus), club moss (Lycopodium clavatum), phosphorus, poison ivy (Rhus Toxicodendron), and rye ergot (Secale Cornutum). However, because of the extreme dilution (or “potentation”) of these ingredient (12C, effectively diluted 1 in 1024) due to the principles underpinning homeopathy (“Law of Infinitesimals”), a litre of Neuragen is only about 50% likely to contain a single molecule of any of the homeopathic ingredients. Any medical explanation of how these homeopathic ingredients work is archaic, implausible, and contradicts our understanding of even basic sciences. So the ingredient list is essentially fairy dust, relying on the idea of “water memory” for its purported effect. So if there are no active homeopathic ingredients, could there be another mechanism for the positive effects reported?

Neuragen also is made up of a propriety blend of geranium oil (Pelargonium graveolens), lavender oil (Lavandula angustifolia), bergamot oil (Citrus aurantium), tea tree oil (Melaleuca alternifolia) and eucalyptus oil (Eucalyptus globulus). Concentrations of each oil are not disclosed. The manufacturer implies these oils act as skin permeators for the homeopathy, but given the homeopathic ingredients have been diluted away, what exactly is permeating? Memory water?

Only geranium oil has any evidence for use in NP.(13) In a letter to the editor, a small controlled trial was reported: Patients had moderate to severe shingles-induced NP, and received a single application of geranium oil. Compared to placebo, they seemed to obtain significant dose-dependent relief of pain after one hour.(14) Interestingly, Origin Biomed, the manufacturer of Neuragen, was a participant in this trial. Unfortunately, there’s insufficient information to properly evaluate the data for the finding to be convincing. Besides this clinical trial, there’s a handful of in vitro and animal trials that suggest this oil may have anti-inflammatory effects. So let’s call this a possible mechanism. The other oils in Neuragen have no scientific evidence demonstrate any effectiveness. However, given they’re all aromatic oils, the scent could give users the perception of effectiveness. It should be noted that Neither Health Canada or the FDA have approved health or safety claims with this product.

The possible side effect profile of these oils, when applied regularly, does raise some questions: Bergamot oil can act as photosensitizer and can induce malignant changes (13), Lavender and tea tree oils have been associated with gynecomastia in prepubertal boys, and undiluted eucalyptus oil can cause neurotoxicity when used topically for prolonged time.(13) Minor adverse reactions to geranium oil include rash, burning sensations, light headedness, and eye irritation.(13) Given the proportions of each oil in Neuragen are not disclosed, there’s no information available to help clarify the risks based on the ingredients alone. Given the possible side effects,children, pregnant or breastfeeding women should avoid this product.(14)

The Evidence

To date, only one trial has evaluated Neuragen for neuropathic pain, in the open-access online journal BMC Complementary and Alternative Medicine.(6) This manufacturer-funded study measured pain in two groups of thirty in a cross-over fashion, for a duration of 8 hours. For most patients, the diagnosis of NP was unknown (idiopathic). One group received Neuragen in a spray formulation, while the other received a mineral oil spray (placebo). Thirty minutes before the applying the product, minutes after and hourly thereafter for eight hours, patients were to rate their pain using standardized scales. A second application was done a week later, where patients “crossed over” or acted as their own controls. According to the author, treatment was considered effective if their pain was reduced by 30% and very effective if there was a 50% reduction.

The author reported “…52% of patients receiving Neuragen PN® achieved a reduction in pain scores of at least 50% compared with 3% of patients receiving the placebo…”. When analyzing the few diabetic patients separately (n=18), it was found that: “…a reduction of pain scores of at least 50% was experienced by 56% of participants with diabetes receiving Neuragen PN® and only 6% of participants with diabetes receiving the placebo…”

Sounds Impressive, but…

Let’s first start with the trial design. This was a single dose trial and provides no information about the use of the product in the real world, where NP is treated for months or years. The investigators used a spray formulation – not the products that are currently sold. We have no information to demonstrate that the same effects might be observed with the dropper bottle or gel. No patients who had shingles or sciatica were included. On top of this, patients used a less accurate personal digital assistant to rate their pain for the post treatment period. This could have influenced the reporting of pain after treatment.

The reporting of results is unclear. The author states in one section that the product provides statistically significant pain relief for “up to 8 hours.”(16) Subsequently, he notes (correctly) that pain reduction “was not significantly different from the placebo between the hours of 5 and 9.”

With a fragrant product, blinding could have been compromised by the odour. Due to the strong floral scent of Neuragen, the investigators tried to control for this by adding fragrance to approximate the smell. They also decided to mask the odor by spraying Neuragen in the room before patients came in for their treatment. The author essentially admits that it’s the oil that is the active ingredient:

It was not possible to replicate the odor of Neuragen PN® exactly in the placebo without replicating its analgesic effects.

The homeopathy would have no odour, so it’s clear the oil is thought to be the active ingredient.

The paper continues:

However, since participants were treated only in a clinical setting, the investigator masked the odors of the treatments by distributing (e.g. spraying) Neuragen PN® in the treatment room before application. This methodology also controlled for any potential mechanism of action involving the effects of fragrance inhalation without topical application to the skin, since all participants were exposed to an approximately equivalent level of odor.

However, patients didn’t stay in the room for eight hours. Leaving the room, the strong fragrance of the product could have easily identified the placebo treatments. Unfortunately, the study does not provide a calculation to see if patients could correctly guess which treatment they received.

Now let’s look a little closer at figure 3, which graphs average pain reduction reported:

Interestingly, you can see the groups differed for only 3.5 hours – after that, there was no significant difference between Neuragen and the placebo. What’s also interesting was that the difference between treatments. Neuragen decreased pain from a reported pain level of 5 to a low of just over 2. The placebo decreased pain to just over 3.

In terms of safety, patients were handed a side-effect form to fill if they experienced something. No adverse events we reported. However, given the author excluded subjects who had any history of unusual skin reactions or allergies, it is not surprising that no one reported apparent effects like skin lesions or itchiness. This is a significant concern for a product that contains ingredients associated with adverse events, and will be used repeatedly. Without longer-term safety data, the true side effect profile is unclear.

Conclusion

Neuragen, despite its advertising, is not true homeopathy. It is a mixture of homeopathic remedies in an aromatic oil base of different oils. If we accept the results of the clinical trial as accurate (despite the numerous limitations), it’s plausible the geranium oil could be providing a therapeutic effect. However, given the significant limitations in the data, and the short duration of the study, the evidence of effectiveness isn’t convincing. Besides the questionable clinical significance, and possibly weak blinding, we’re left with a clinical trial result for a product that may not be the same as the products currently sold.

This study does not provide persuasive evidence of long-term effectiveness or safety. Neuropathic pain is already hard to manage and patients suffer tremendously as a result. New therapies — “natural” or otherwise — with few side effects are needed for this common condition. However, patients need science based treatments based on adequate controlled trials, which are of sufficient power, with better methods, and tested for at least a few months. Fortunately, a new trial of Neuragen set to finish in January 2011 looks like it may resolve some of the strong limitations in the BMC trial.

Neuragen has not been approved for sale Health Canada’s Natural Health Products Directorate. What this means is it is not permitted for sale in pharmacies. Despite this, it is widely available. Health professionals who strive for a science based practice would do well to consider the numerous limitations in the clinical efficacy and safety data before recommending this product.

References

1. Moulin DE, et al. (2007). Pharmacological Management of Chronic Neuropathic Pain, Consensus Statement and Guidelines from the Canadian Pain Society. Pain Res Manage, 12(1), 13-21.

2. Foley KM. (2003). Opioids and Chronic Neuropathic Pain. N Engl J Med, 348, 1279-1281.

3. Van Acker K, et al. (Jun 2009). Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab, 35(3), 206-213. Epub Mar 17, 2009.

4. Sampathkumar P, et al. (Mar 2009). Herpes zoster (shingles) and postherpetic neuralgia. Mayo Clin Proc. 84(3), 274-80.

5. Origin Biomed website, Neuragen.com: http://www.neuragen.com/professional.php Retrieved September 2010.

6. Li, L. (2010). The effect of Neuragen PN® on Neuropathic pain: A randomized, double blind, placebo controlled clinical trial BMC Complementary and Alternative Medicine, 10 (1) DOI: 10.1186/1472-6882-10-22

7. Peripheral Neuropathy, Dynamed, last updated 2010 May 28 10:44 AM

8. McBean Cochran B. (Jun 2009). The Role of the Pharmacist in the Management of Chronic Neuropathic Pain. Continual Education Lesson. Rogers Publishing Limited (Pharmacy Group)

9. Fields HL, & Martin JB. (2010). Harrison’s Online. Part Two: Cardinal Manifestations and Presentation of Diseases. Section 1: Pain. Chapter 12. Pain: Pathophysiology and Management. Retrieved August 4, 2010.

10. Saarto T, & Wiffen PJ. (2007). Antidepressants for neuropathic pain. Cochrane Database of Systematic Reviews. Issue 4. Art. No.: CD005454. DOI: 10.1002/14651858.CD005454.pub2

11. Moore RA, et al. (2009). Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews. Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2.

12) Wiffen PJ, et al. (2005). Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews. Issue 3. Art. No.: CD005452. DOI: 10.1002/14651858.CD005452.

13. Natural Medicine Comprehensive Database, accessed on 18-08-2010

14. Greenway FL, et al. (Nov 2003). Temporary relief of postherpetic neuralgia pain with topical geranium oil. Am J Med, 115(7), 586-587.