Anti Epileptics For Neuropathy An Australian View

Today's post from nps.org.au (see link below) is a very interesting look at the workings of anti-epileptic drugs in the treatment of neuropathy. It's always interesting to look at how different countries approach the treatment of chronic pain and/or neuropathy. In Australia, it's generally recommended that neuropathy patients are treated with a progressive scale of treatments, beginning with non-drug options and moving on, if necessary, via anti-depressants and anti-epilepsy drugs to opiates. This ties into a general world-wide approach to the disease but the article agrees that neuropathy is hard to treat, whatever you use to control the symptoms. Regarding anti-epileptic drugs, it concludes that the only two that are effective (however limited) are gabapentin and pregabalin. However, once again, this ignores Pfizer's own advice that pregabalin (Lyrica) is not suitable for particular groups of neuropathy sufferers (HIV- and diabetic neuropathy patients for instance) and it does seem strange that that advice from the makers is being overlooked across the world. This may partly be due to that fact that doctors see some successes with neuropathy patients being treated with Pregabalin but that doesn't take into account whether the drug is actually good for you or not. Whatever the issues around pregabalin, this is an interesting article for those already on anti-epileptics, or about to begin using them.

Treating neuropathic pain with anticonvulsants — which ones work?
Published in Health News and Evidence Date published: 10 January 2014

Summary
 
Neuropathic pain is a common form of chronic pain, with an array of drugs available for its treatment, including anticonvulsants.

A recent Cochrane review assessed the evidence around efficacy and safety for 10 anticonvulsant drugs used to treat neuropathic pain and found evidence of efficacy for only 2 — gabapentin and pregabalin.
The study provides support for the use of pregabalin and gabapentin in treatment of neuropathic pain, but was not able to distinguish between the 2 drugs in terms of efficacy for the treatment of painful diabetic neuropathy or postherpetic neuralgia. Nor was the study able to identify patients most likely to benefit from treatment with either drug.
Gabapentin and pregabalin are TGA-approved in Australia for the treatment of neuropathic pain. Currently, pregabalin is PBS subsidised when prescribed for neuropathic pain, and gabapentin is subsidised for this indication only under the RPBS. 

Practice points
Use a comprehensive clinical assessment to determine the cause of pain, its nature and severity, and the effect of the pain on the patient.1
Provide each patient with an individual management plan based on this assessment.1
Use a multidisciplinary approach to management that includes patients in decision making, and consider non-drug treatments first.1,2
Consider the TCA amitriptyline as first line if drug treatment is required.3
Consider next an anticonvulsant such as pregabalin or gabapentin if first line is unsuccessful.3
Conduct early and regular clinical reviews of patients on drug treatment.4
Refer patients whose pain relief is inadequate to a pain specialist, a multidisciplinary pain clinic or a palliative care service.3,5
Chronic pain in Australia

Chronic pain affects 1 in 5 Australian adults,6,7 with incidence increasing with age. Much of the burden of patient management falls on general practitioners.1

Chronic pain is Australia's third most costly health condition after cardiovascular diseases and musculoskeletal conditions.8 The total cost of chronic pain to the Australian economy was reported to be $34 billion in 2007, including $7 billion in health system costs.8

Neuropathic pain

Neuropathic pain is a form of chronic pain, and is difficult to treat effectively.3

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system9 and is usually described as burning, painful, cold or electric shocks. These symptoms may occur alongside tingling, pins and needles, numbness or itching.3,10

Causes include nerve damage, which can be followed by changes to the central nervous system.11 This condition can present for months or years, causing significant, disabling, moderate to severe pain.11
Neuropathic pain: Australian guidelines

Australian guidelines recommend that patients with chronic pain, such as neuropathic pain, have an individualised management plan. This plan should be linked to a comprehensive patient assessment to determine the cause of pain, its nature and severity as well as the effect of the pain on the patient.1

There is no generally accepted 'stepwise' approach to treatment of neuropathic pain. Australian guidelines recommend non-drug approaches first.1,5 Many drugs are available for the treatment of neuropathic pain, with TCAs and anticonvulsants the drugs of choice.3,5 However, comparative studies are limited, there is no evidence for differences in the relative efficacies of individual drugs5,11 and these treatments are often associated with adverse events.

Guidelines recommend starting drug therapy for neuropathic pain with a TCA (such as amitriptyline) or an anticonvulsant.3,5 The anticonvulsants gabapentin and pregabalin are recommended by Therapeutic Guidelines as a second-line treatment of neuropathic pain after the TCA amitriptyline.3 The dose of the drugs can be escalated at weekly intervals if tolerated, but it may take several weeks to achieve clinical efficacy.

*TCAs are an established treatment for neuropathic pain but are not approved by the TGA for this indication.
Efficacy and safety of anticonvulsant drugs for neuropathic pain: Cochrane review

The Cochrane Collaboration recently reviewed the efficacy and safety of 10 anticonvulsant drugs for the treatment of neuropathic pain and fibromyalgia.11 This was not a new systematic review of individual studies,11 but compiled data from the 10 previous Cochrane reviews published between 2009 and 201312-21 and comprising 17,955 participants (with at least moderate pain) from 91 studies.11-21

These studies were placebo controlled, double blind, randomised controlled trials. Results were presented for each different drug for 3 different neuropathic pain conditions — painful diabetic neuropathy, postherpetic neuralgia and central neuropathic pain — and for fibromyalgia. This article will focus on the findings related to neuropathic pain.

Evidence of pain reduction for gabapentin and pregabalin only

This Cochrane review reported on efficacy as well as patient impression of improvement, and investigated outcomes including patient-reported pain relief of 50% or more and Patient Global Impression of Change (PGIC).11 Results were reported in terms of whether patients were more likely to achieve the benefit with the treatment than by taking placebo.11

A reduction in pain intensity of 50% or more is considered to be a clinically relevant benefit.3

The Patient Global Impression of Change (PGIC) is a measure of global improvement with treatment where participants rate their improvement from 'very much improved' to 'very much worse' with 'no change' as the mid-point.22

Among the 10 anticonvulsants studied, evidence of pain reduction was only found for gabapentin and pregabalin.11 People taking either of these drugs were more likely to report pain relief of 50% or more for painful diabetic neuropathy and postherpetic neuralgia than those taking placebo†.11 People taking pregabalin for the treatment of central neuropathic pain were also more likely (compared to placebo) to report pain relief of 50% or more†.11

The number of patients who would need to be treated with pregabalin or gabapentin for one patient to see this improvement was estimated to range from 4 to 10 for >=50% reduction in pain.11 Therapeutic Guidelines advises that for pain treatment to be considered to be effective, the number needed to treat for one person to achieve an outcome should be between 2 and 5.3
Further findings

The Cochrane review also found that people taking gabapentin for painful diabetic neuropathy or postherpetic neuralgia were more likely to rate their improvement as 'excellent' or 'very good or excellent' than those people taking placebo*.11

People taking lacosamide or pregabalin for painful diabetic neuropathy were more likely to rate their improvement as 'very good or excellent' than those people taking placebo*.11 The data suggest that the benefit with pregabalin may be dose dependent, as a benefit was seen with the 600mg/day dose but not the 300mg/day dose. Data for other drugs was not presented.11
*These results were statistically significant. The rating of improvement by patients was determined using the PGIC.

Carbamazepine: an accepted treatment for neuropathic pain but insufficient evidence of effect

Carbamazepine is an accepted treatment in Australia for neuropathic pain but is not TGA-approved for this indication.5

This Cochrane review found that evidence of efficacy for carbamazepine was of low quality and consequently likely to be subject to a number of biases that would overestimate efficacy.11 Most studies with carbamazepine were less than 4 weeks' duration, in contrast to studies with other drugs that were of 10-12 weeks or longer.11
Safety

The risk of adverse events in people taking anticonvulsant drugs is high, with CNS adverse events relatively common and often dose dependent, particularly for pregabalin and lacosamide.11 In this Cochrane review, available data showed that only oxcarbazepine statistically significantly increased the risk of a serious adverse event in people taking anticonvulsants for either neuropathic pain or fibromyalgia compared to those taking placebo.11

Limitations of the study

This Cochrane review benefits from, and is also limited by, the fact that the data are taken solely from previous Cochrane reviews. While this ensures that each study included is of a comparative and high standard, it also means that some trials would have been omitted.11 For example, levetiracetam does not feature in a Cochrane review and therefore was not assessed in this study, although it has been tested in other randomised controlled trials.11
Conclusions: pregabalin and gabapentin are the preferred anticonvulsants

While all evidence considered in this Cochrane review was described as 'second tier' or lower due to the potential for biases to overestimate efficacy, the results provide support for current Australian guidelines.3
Treatment best practice and implications for patients
Assess the nature of the pain experience and inform people of realistic outcomes with treatment.23,24
Provide each patient with an individualised management plan based on a comprehensive clinical assessment of their pain.1
The primary treatment goal in most cases is to make the pain tolerable — not usually to eliminate the pain.23
Aim for medium-term drug therapy with a drug holiday after 6 months. Patients who relapse during a drug holiday can resume treatment.
Conduct early and regular clinical reviews.

This Cochrane review supports the use of pregabalin and gabapentin as part of a management plan for neuropathic pain, but is not able to distinguish between their efficacies for treatment of painful diabetic neuropathy or postherpetic neuralgia. Drug therapy is best used as part of a multifaceted, multidisciplinary, active self-management approach to the physical, psychological, social and vocational impacts of neuropathic pain.2

Analgesic failure is common in the treatment of neuropathic pain and there is currently no evidence to inform which patients are most likely to benefit from what drugs and indeed the order in which drugs should be taken to optimise outcomes.11 However, patients who do not respond to one drug may respond to another, even within the same drug class.5 Combination drug therapy may be needed by many patients.24,25 A specific combination of treatments cannot be recommended due to the limited number of studies for any combination therapy, as well as other study factors, such as the limited trial size and duration.25

More information is available from NSW Health.

Refractory, severe neuropathic pain

Assistance from a pain specialist and a multidisciplinary pain service may be required for refractory, severe neuropathic pain, as treatment options are complex.2
Further information
Pregabalin (Lyrica) for neuropathic pain (NPS Medicinewise RADAR: April 2013).26
Information for patients

Patient information leaflet: Key points for patients about chronic pain (Therapeutic Guidelines).

References

1. eTG complete [Internet]. Therapeutic Guidelines: Analgesic. Melbourne: 2012. [Online] (accessed 19 December 2013).
2. Australian Pain Society. Evidence-based recommendations for the pharmacological management of neuropathic pain. Position Statement, June 2008. [Online] (accessed 20 October 2012)
3. eTG complete [Internet]. Therapeutic Guidelines: Neurology. Melbourne: 2011. [Online] (accessed 19 December 2013).
4. National Institute for Clinical Excellence (Nice). Neuropathic Pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. NICE Clinical Guideline 173. Manchester: National Institute for Clinical Excellence, 2013. [Full text]
5. Rossi S e. Australian Medicines Handbook, 2013. Adelaide.
6. Hogg MN, Gibson S, Helou A, et al. Waiting in pain: a systematic investigation into the provision of persistent pain services in Australia. Med J Aust 2012;196:386-90. [PubMed]
7. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain 2001;89:127-34. [PubMed]
8. Access Economics Pty  Ltd. The high price of pain: the economic  impact of persistent pain in Australia. Sydney Deloite Access Economics, 2007 [Full text]
9. Jensen TS, Baron R, Haanpaa M, et al. A new definition of neuropathic pain. Pain 2011;152:2204-5. [PubMed]
10. Votrubec M, Thong I. Neuropathic pain — a management update. Aust Fam Physician 2013;42:92-7. [PubMed]
11. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia — an overview of Cochrane reviews. Cochrane Database Syst Rev 2013;11:CD010567. [PubMed]
12. Birse F, Derry S, Moore RA. Phenytoin for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009485. [PubMed]
13. Corrigan R, Derry S, Wiffen PJ, et al. Clonazepam for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009486. [PubMed]
14. Gill D, Derry S, Wiffen PJ, et al. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD009183. [PubMed]
15. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;2:CD009318. [PubMed]
16. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009:CD007076. [PubMed]
17. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD007938. [PubMed]
18. Wiffen PJ, Derry S, Lunn MP, et al. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013;8:CD008314. [PubMed]
19. Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2011:CD006044. [PubMed]
20. Wiffen PJ, Derry S, Moore RA, et al. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev 2011:CD005451. [PubMed]
21. Zhou M, Chen N, He L, et al. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2013;3:CD007963. [PubMed]
22. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19. [PubMed]
23. Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13-21. [PubMed]
24. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-14. [PubMed]
25. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev 2012;7:CD008943. [PubMed]
26. National Prescribing Service. Pregabalin (Lyrica) for neuropathic pain. RADAR; April 2013. [Full text]

http://www.nps.org.au/health-professionals/health-news-evidence/latest-issue/treating-neuropathic-pain

Weight Bearing Exercise Can Be Dangerous For Neuropathy Patients

Today's post from huffingtonpost.com (see link below) looks at the problems that certain forms of exercise may bring the neuropathy patient who has lost most of the feeling in their feet. These problems are not to be underestimated but it's important to say here that the vast majority of neuropathy patients have some feeling in their feet, despite the numbness that can affect the toes and pads of the foot. These patients are unlikely to step on a nail and not feel something. That said, many people living with neuropathy feel very little and this can certainly lead to serious accidents. When this is the case, load-bearing exercises can be more dangerous than helpful. Nevertheless the article recommends exercise as being essential, as long as this is controlled and the feet are carefully and regularly monitored. The article is aimed at diabetic neuropathy patients but applies to all people living with neuropathy and foot problems.

Type 2 Diabetes and Peripheral Neuropathy: To Walk or Not to Walk?
 
Milt Bedingfield Posted: 05/11/2015 

It is now well known that engaging in light to moderate physical activity on a regular basis is of significant value for most people that have either Type 1 or Type 2 diabetes. In fact the American Diabetes Association recommends that people with diabetes should get a minimum of 150 minutes of light to moderate exercise per week including aerobic and resistance training.

What the ADA says...

It has also been recommended that people with peripheral diabetic neuropathy that have reduced or absent feeling in their feet should not engage in any form of weight bearing exercise activity. The American Diabetes Association recommends that people with diabetes-related peripheral neuropathy should limit the amount of weight-bearing physical activity they perform due to their increased risk of foot ulcers and amputation (1, 2). This is based on the fact that with peripheral neuropathy there is either a decreased ability or total inability in the feet to feel pain or discomfort.

As an example, standing barefoot on hot asphalt maybe in a parking lot in the middle of the summer would be very uncomfortable for someone with normal sensation in their feet, however go unnoticed for someone with peripheral neuropathy. Similarly, the person with peripheral neuropathy may develop a painful nickel-sized blister after walking too far or when wearing new shoes and not even feel it. Without daily inspection of the ankles and feet (which a lot of people do not do) this blister could go unnoticed for days resulting in a potentially infected, slow to heal, or non-healing wound. In the worst case this could lead to an amputation. All of this is the result of losing what is called the protective sensation in the feet.

In the absence of peripheral neuropathy whenever there is insult to the foot or feet such as a blister, a cut or scrape or stepping on a small piece of glass or nail, there would be pain which would cause you to notice the injury and hopefully treat the wound accordingly.

There are also painful stages of neuropathy that can precede lack of sensation which are characterized by frequent but intermittent pain in the feet throughout the day, having pain only in the evening while in bed to constant pain. This stage of neuropathy can result in changing the way you walk, that is your stride length, which part of your feet you strike the ground with first and ultimately what part of your feet support your body weight.

Because of everything I have just mentioned above this leads to the unfortunately recommendation that discourages walking for a great many people with diabetes.

To Walk or Not to Walk?

So where does that leave us? Exercise is arguably the best treatment there is, particularly in controlling Type 2 diabetes, and preventing diabetes related complications, such as peripheral neuropathy, however once you have peripheral neuropathy in your feet you should avoid doing any weight bearing exercise.

I have wrestled with the dilemma for years about how to guide my patients that would benefit immensely from starting to exercise or increasing their exercise however have various stages of neuropathy.

According to the Centers for Disease Control and Prevention, from 2000-2002, approximately 60 percent of lower-extremity amputations in the United States were diabetes-related, with the majority of those amputations being preceded by a foot ulcer (3). Almost all diabetic foot ulcers occur in those people that have lost feeling in their feet due to diabetic peripheral neuropathy (4, 5).

On the other hand poorly controlled blood glucose control contributes greatly to peripheral neuropathy.

Eight-year cardiovascular mortality is 34 percent lower among people with diabetes who walk two hours per week compared with non-walkers (6).

Feet First Randomized Controlled Trial

The Feet First Randomized Controlled Trial was designed to look at the effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy. The study, conducted over a 12-month period by Lemaster and colleagues, showed that participants in the Feet First intervention group achieved a modest increase in activity, with no increase in foot lesions, compared with those in the control group. The group also recommended additional research be conducted in this area to investigate the current guidelines and close supervision for patients with diabetes and peripheral neuropathy (7).

Tuttle and colleagues found that people with Type 2 diabetes and peripheral neuropathy experienced no negative consequences when performing moderate-intensity, weight-bearing exercise in their study (2).

Dr. Sheri Colberg reports in her article "Exercising with Peripheral Neuropathy" that recent descriptive studies suggest that patients with a lack of feeling in their feet who participate in daily weight-bearing activity are at decreased risk of foot ulceration compared with those who are less active (8, 9), especially if their daily routine is very similar with little variation from day to day regarding their physical activity (9, 10).

As a result of the above information, I am going to continue evaluating each of my class participants on a case by case basis, however, for those patients with peripheral neuropathy that I believe will be prudent in checking their feet and following the recommended foot care guidelines and stand to gain significant benefit from performing some weight bearing exercise, I will be more likely to recommend it to them.

References:

1. Singh, N., D. G. Armstrong, and B. A. Lipsky: Preventing foot ulcers in patients with diabetes. JAMA 293 (2):217-228, 2005

2. Tuttle, L. J., M. K. Hastings, and M. J. Mueller: A moderate-intensity weight-bearing exercise program for a person with Type 2 diabetes and peripheral neuropathy. Phys Ther 92 (1):133-141, 2012

3. Centers for Disease Control and Prevention. History of foot ulcer among persons with diabetes -- United States, 2000-2002. MMWR. 2003;52:1098-1102. Medline

4. Pham H, Armstrong DG, Harvey C, et al. Screening techniques to identify people at high risk for diabetic foot ulceration: a prospective multicenter trial. Diabetes Care. 2000;23:606-611.

5. Reiber GE, Smith DG, Wallace C, et al. Effect of therapeutic footwear on foot reulceration in patients with diabetes: a randomized controlled trial. JAMA. 2002;287:2552-2558. CrossRefMedline

6. Gregg EW, Gerzoff RB, Caspersen CJ, et al. Relationship of walking to mortality among US adults with diabetes. Arch Intern Med. 2003;163:1440-1447. CrossRefMedline

7. Lemaster, J. W., M. J. Mueller, G. E. Reiber, D. R. Mehr, R. W. Madsen, and V. S. Conn: Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Phys Ther 88 (11):1385-1398, 2008

8. Richerson, S., and K. Rosendale: Does tai chi improve plantar sensory ability? A pilot study. Diabetes Tech Ther 9(3):276-286, 2007

9. Ko, S. U., S. Stenholm, C. W. Chia, E. M. Simonsick, and L. Ferrucci: Gait pattern alterations in older adults associated with type 2 diabetes in the absence of peripheral neuropathy--results from the Baltimore Longitudinal Study of Aging. Gait Posture 34 (4):548-552, 2011

10. Kanade, R. V., R. W. van Deursen, K. Harding, and P. Price: Walking performance in people with diabetic neuropathy: benefits and threats. Diabetologia 49 (8):1747-1754, 2006

http://www.huffingtonpost.com/milt-bedingfield/post_9394_b_7188266.html

Duloxetine Cymbalta Reviews For Neuropathy

Today's post from the always reliable Drugs.com (see link below) talks about user reviews of Duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela), which is an antidepressant drug used to treat neuropathy. It's a somewhat controversial drug due to the potential side effects which many people just can't take.The reviews are not extensive and not really up to date, which is why this post asks for your input. Drugs.com is always a trustworthy source for information about any drugs you may take and is worth adding to your favourites, especially when you are taking multiple drugs for different conditions.
If you are taking Duloxetine/Cymbalta, or have taken it in the past, please share your experiences for the benefit of others, especially in comparison with other anticonvulsant or antidepressant drugs prescribed for neuropathy.

User Reviews for Duloxetine
Also known as: Cymbalta

The following information is NOT intended to endorse drugs or recommend therapy. While these reviews might be helpful, they are not a substitute for the expertise, skill, knowledge and judgement of healthcare practitioners in patient care.
Learn more about Duloxetine.

Compare all 38 medications used in the treatment of Diabetic Peripheral Neuropathy.

Reviews for Duloxetine to treat Diabetic Peripheral Neuropathy


Review by Anonymous (taken for less than 1 month):January 25, 2013 11:21 AM User Rating: 8.0

Cymbalta (duloxetine): I’m a Type 1 Diabetic for 39 years. Had VERY painful muscle spasms/seizing and twitching. I tried various supplements which "should" have helped but no improvement. I started Neurontin at 1,800mg/day and I had terrible swelling plus gained 18 lbs in 6 months (and my eating habits actually got better while on it). The 1,800mg of Neurontin no longer controlled the muscle spasms. I started Cymbalta, 30 mg before bed, and had significant reduction in pain the first morning. I did notice a very strong headache that first day. I had only 3-4 muscle spasms that first day as well....Wow!! Second day...almost NO pain in the morning and only a dull headache with much weaker muscle spasms. Side effects: Crazy dreams, difficulty sleeping, headache.

Review by Anonymous (taken for 1 to 2 years): September 14, 2012 

User Rating: 9.0

Cymbalta (duloxetine): I was not sure how well it worked at first. Then I was unable to get it for awhile, and was in a lot of pain, trouble getting through the day. I just wanted to sleep. Once back in my system I noticed the difference. This helps my depression, back pain, and the neuropathy.

Review by Anonymous:August 12, 2012 10:37 AMUser Rating: 1.0

Cymbalta (duloxetine): Did not work for me. I had nausea, abdominal & stomach pain, loss of appetite. I lost 5 lbs. in less than a week.


Review by Tonywwk1:March 23, 2012 4:51 PMUser Rating: 8.0

duloxetine: I have severe Diabetic Neuropathy to both feet, and Neurotin seemed rather ineffective. The pain was a combination of burning, needles and pins sensation, and severe knife stabbing sensations intermittently to both feet. I started taking Cymbalta over a year ago, and it has significantly reduced the sensations and pain, making them tolerable. I initially noticed a loss of appetite, which was a blessing in disguise for me, and I lost 25 pounds before the anorexia disappeared. I have several severe disorders which require close monitoring of my blood, but overall, Cymbalta has been a God send to me.

Review by Sewanhaka100: February 18, 2012 1:23 AM

Cymbalta (duloxetine): I started on 30mg Cymbalta daily with a little foot pain improvement - as this was still not enough my doctor put me on 60mg daily. I am so happy and relieved to be able to actually "walk" again and function like a normal person. I was crawling to the bathroom at night before for 8 months I was in pure agony. I have been on Cymbalta for 5 weeks and so far great results! Thank you Eli Lilly and my doctor.

Review by Anonymous: September 6, 2010 7:28 PMUser Rating: 8.0

Cymbalta (duloxetine): Cymbalta lessens the burning pain in my feet that used to wake me up and keep me awake at night. It often relieves burning pain almost completely.

Review by kathygirl: August 6, 2010 10:50 AM 

User Rating: 3.0

Cymbalta (duloxetine): I was very unsteady on my feet, at first some of the pain was resolved, but it didn't work. Even though my feet were NOT swollen they felt that way, very tight feeling. It felt like I was walking on balloons, terrible feeling and I was afraid to walk with that unsteadiness. Didn't work for me, since then, I have been on many different medications. Neurontin, didn't help, amitriptiline, didn't help, Lyrica, didn't help. I am on nortriptyline now with a pain patch. The fentanyl patch really helps, but I don't want to stay on this forever, so trying different medications. I am only supposed to leave the pain patch on 3 days, and found with the new medication, nortriptyline, I can go 5 days. So I am hopeful here.

Review by Anonymous: February 1, 2010 1:25 PM
User Rating: 8.0

Cymbalta (duloxetine): I have peripheral neuropathy and very bad pain in my back. Cymbalta made a huge improvement in my pain level. The doctor started me gradually to lessen the nausea. I have worked up to 30 mg. twice a day for a total of 60 mg. I have been taking it for 3 months and still find the pain level, and my frame of mind, much improved. I do have slight nausea occasionally, and dry mouth. The excessive sweating has gone away.

Review by Jo.Nigle: October 27, 2009 5:22 AM 

User Rating: 9.0

Cymbalta (duloxetine): Cymbalta was the first drug that actually improved the diabetic neuropathy pain I was experiencing in my legs, feet, arms and hands. For the first time, I was able to sleep through the night without waking in tears from the pain. I was so happy my doctor put me on this drug in conjunction with Neurontin. The pain almost disappeared! Approximately 6-8 weeks later, I noticed that the neuropathy pain started back up again despite continuing on the medicines. I too, had insomnia making it difficult, at best, to be alert, focused or have any energy the following day. To this day, I still have some insomnia and an increase in the neuropathy symptoms; BUT Cymbalta 60mg & Neurontin 600mg are the BEST drugs so far in lessening the pain.

Review by TerryinAlaska: October 20, 2009 6:45 PM 

User Rating: 3.0

Cymbalta (duloxetine): It was like a wonder drug at first. Then, even though I went up to the maximum dose of 60 mg, I can no longer tell I am even taking it. I stop it - then start it back up - still no help. It's just no good anymore.

Review by Tomasue: September 4, 2009 5:38 PM 

Cymbalta (duloxetine): I was only able to take this for about 3 days. It made me so unsteady on my feet that falling was a great threat. I also spoke, looked and felt like a "drunken sailor". Totally uncoordinated and 'out of it'. It did nothing for my neuropathy.

Review by KimberDawn38: July 25, 2009 5:09 AM 

User Rating: 10

Cymbalta (duloxetine): I've tried many, many different medicines for my nerve pain. Finally after being put on Cymbalta for my depression, I noticed that my nerve pain was not near as bad as it was before. I'm overwhelmed with my results. Almost to tears, of joy, instead of tears of pain! Thank you!

Review by HAPPYKAT: June 26, 2009 11:24 PMUser Rating: 10

Cymbalta (duloxetine): Works great on my nerve pains, due to diabetes.

Review by Anonymous: June 11, 2009 4:10 PM

Cymbalta (duloxetine): Cymbalta worked for my neuropathy for about 6 weeks then suddenly stopped working. I was very sad that is stopped. I did experience very bad insomnia but other than that I didn't have any major side effects.

Review by Anonymous: June 9, 2009 3:43 PMUser Rating: 1.0

Cymbalta (duloxetine): Debilitating side effects after only 2 hours with only one 60mg pill. Extreme sweating, fatigue, difficulty swallowing and walking. Next came the nausea and intense insomnia. Had to call in sick to work the next day due to lack of sleep and weakness. Didn't get out of bed until 3 pm.

Review by hemaro: April 6, 2009 7:01 PM

User Rating: 9.0

Cymbalta (duloxetine): Cymbalta has been a lifesaver for my Diabetic Neuropathy. In just a few days the pain and discomfort went away. The only problem I am facing with Cymbalta is insomnia even in combination with Xanax 4mg and Vistaril 150mg.

Review by Anonymous: February 25, 2009 9:25 PM
User Rating: 9.0

Cymbalta (duloxetine): Caused me to have serotonin syndrome.
..................................................................................................................................

http://www.drugs.com/comments/duloxetine/for-diabetic-neuropathy.html

Calcium For Neuropathy Vid

Today's video from the ever informative beatingneuropathy.tv (see link below) produced by Dr John Hayes Jr, talks about the value of calcium in relation to neuropathy. These videos are short and always worth watching whatever your views on supplements are.



Episode 31 – Calcium
Posted by John Hayes Jr Thursday, October 24th, 2013

Dr. Hayes discusses calcium, possible issues with supplementation, and how neuropathy and chronic pain patients can make sure they’re getting enough. This is one nutrient that the truth is often not what it seems with powerful media driven economics behind it. Watch and learn More!




http://beatingneuropathy.tv/2013/10/episode-31-calcium-neuropathy/

Is Massage Really Wise For Neuropathy

Today's post from painscience.com (see link below) warns about the possible disadvantages of massage therapy. Many people with neuropathy symptoms somehow assume that massage will help them feel better and in many cases they do but you need to go to a massage therapist who knows what he or she is doing. The idea that you may come away with symptoms that are worse than before should be enough to make you think about whether a good pummelling is really good for your nerves or not. Gentle massage may well be very effective in calming down painful nerve areas, or generally making you relax but the minute the masseur goes for deep tissue and joint massage may be the moment you ask how much experience he or she has with neuropathy. You probably know yourself, if you've tried massaging your neuropathic feet. Half the time you can't feel anything due to the numbness but the moment you push just that little bit too hard to relieve the burning or tingling, you can be suffering for days. Always best to go to a qualified masseur with relevant experience, or else the happy ending may not be as happy as you thought (goes for all kinds of massage!!)
 

What Could Possibly Go Wrong With Massage?
Rare but real adverse effects of massage therapy, especially “deep tissue” massage
updated July 16 2014 by Paul Ingraham, Vancouver, Canada bio

People think of massage therapy as a “safe” therapy, and of course it mostly is. But things can go wrong, or at least a bit sour. While serious side effects in massage therapy are extremely rare, minor side effects are downright common. A 2007 survey of 100 massage patients1 found that 10% of 100 patients receiving massage therapy reported “some minor discomfort” in the day following treatment. This would mainly be a familiar slight soreness that is common after a massage, known as “post-massage soreness and malaise” (PMSM) — and I’m surprised only 10% reported it. The massages they were getting must have been quite gentle.2

Interestingly, 23% reported unexpected benefits that had nothing to do with aches or pains. (Benefits for musculoskeletal problems were not documented.)

This study is underpowered. It cannot and does not rule out rare and/or serious side effects of massage therapy, which do exist. You could probably do several studies of 100 patients without encountering a single nasty situation. But what if you surveyed 1,000 patients? Or 10,0000? Massage is not completely safe — what is? — and other adverse effects would almost certainly turn up in a big enough survey. Nevertheless, according to one of alternative medicine’s most vigorous critics, Dr. Edzard Ernst, “Serious adverse events are probably true rarities.”3 And yet, reviewing the literature again in 2013, Ernst and Posadzki found at least 18 reported examples of “moderately severe” reactions to normal massage, especially of the neck.4
When massage goes bad

So what could possibly go wrong? Massage can…
directly cause new injuries (mostly quite minor, but not all)
aggravate existing injuries and chronic pain problems
distract patients from more appropriate care
mildly stress the body And don’t forget, of course, that that pointlessly draining your wallet is another kind of pain. If someone spends $5,000 on massage therapy that has only a minor therapeutic effect, or none at all, is that an “injury”? It’s an insult, at the least!

In my decade (2000–2010) as a massage therapist, I met many patients who had been harmed by massage therapy to some degree — fortunately, mostly just expensive disappointments and minor backfires, but quite a few more serious cases too.5 

Sensory injury

A painful, alarming sensory experience can actually dial up pain sensitivity — even long term.6 Furthermore, vulnerability to this awful phenomenon is much more common and significant in desperate patients who already have chronic pain — so they seek and tolerate intense therapy. People experiencing pain system dysfunction can have minor & major setbacks in response to excessively painful massage.

The experience of pain is affected by many factors, including emotional and psychological ones. People in chronic pain usually experience some degree of pain neurology dysfunction, and a breakdown of the relationship between how bad things feel and how much is really wrong. That breakdown can be seriously worsened by threatening sensations. Thus, people experiencing pain system dysfunction can have minor and major setbacks in response to excessively painful massage.

One of my readers suffered this kind of disaster. She was injured by “fascial release” therapy, a style which is often too intense and may focus on treating connective tissues to the exclusion of considering the patient’s comfort and nervous system.

I may have been too aggressive with a few patients over the years. I never did serious harm this way as far as I know, but I’m sure that I occasionally did more harm than good. This failure was due entirely to my ignorance of pain science: despite being an unusually well educated massage therapist, I simply did not know that an intense massage could change pain sensitivity itself. Does your therapist?
Pain is Weird Pain science reveals a volatile, misleading sensation that is often more than just a symptom, and sometimes worse than whatever started it ~ 9,000 words
The Pressure Question in Massage Therapy What’s the right amount of pressure to apply to muscles in massage therapy and self-massage? ~ 4,500 words
Poisoned by massage

Excessive pressure probably has another predictable outcome: a light poisoning. Seriously.

For example: an 88-year old man collapsed the day after an unusually strong 2-hour session of massage therapy.7 He had too much myoglobin in his blood, and it was poisoning his kidneys and generally making him feel rotten. It’s not a sure thing that his condition was cause by the massage — but it is quite likely. It is almost certainly a perfect example of one of those rare but serious complications of massage. Another case study comes up below.

Ironically, many people believe that massage is a detoxification treatment, but in fact it’s probably the opposite. Ironically, many people believe that massage is a detoxification treatment, but in fact it’s probably the opposite. Post-massage soreness and malaise is probably caused by mild rhabdomyolysis (“rhabdo”): poisoning by the waste products of injured muscle.

True rhabdo is a medical emergency in which the kidneys are poisoned by myoglobin from muscle crush injuries. But many physical and metabolic stresses cause milder rhabdo-like states — even just intense exercise, and probably massage as well. There are many well-documented cases of exertional or “white collar” rhabdo, and there is a strong similarity between PMSM and ordinary exercise soreness. A rhabdo cocktail of waste metabolites and by-products of tissue damage is probably why we feel a bit cruddy after all biological stresses and traumas — including massage, sometimes.

PMSM is just an unavoidable mild side effect of strong massage. And for a few more vulnerable patients, it could actually be a little dangerous.
Poisoned by Massage Rather than being “detoxifying,” massage may cause a modestly toxic situation in the body ~ 4,500 words 

Other examples of massage wounds

The neck is not generally a fragile structure, but it is in some people. Another serious example of an adverse effect of massage is what happened to my barber — either a brain stem injury or mini-stroke caused by careless massage of a vulnerable neck. One of my own patients was injured the same way by another therapist, vomiting and retching for hours afterwards (a nasty symptom of brain stem impingement, or ripping of an artery going to the brain). I came close to doing this to another patient — that’s three examples of such patients in my career — but I’m proud to say that I spotted the warning signs and avoided disaster.

A weird case of brain artery damage (extracranial internal cartoid artery dissection, specifically) was reported in 2004 by the Southern Medical Journal: a 38-year-old woman gave herself a stroke by using a vibrating massage tool for long and too hard on her neck.8 Obviously such an incident has little to do with professional massage. Nevertheless, it demonstrates that the arteries of the neck are a little bit fragile — and I have no doubt that there are poorly trained or incompetent therapists out there would might get carelessly exuberant in this region, while trying to treat the scalenes: see Massage Therapy for Neck Pain, Chest Pain, Arm Pain, and Upper Back Pain.

Another weird, extreme case study paper tells the horror story of one person’s awful experience with a severe reaction to (apparently) infrared heat and massage therapy.9 The trouble started after several treatments. His neck and arms were swollen, the pain became “unbearable,” and his “serum muscle enzymes were increased” — which means some degree of rhabdo, which implicates the massage itself as a significant mechanism of injury. Massage is not likely to “blame” for the incident, though — it was probably interacting with some unidentified vulnerability in the patient, such a muscle disease or a complication caused by a medication. Clearly massage and heat alone do not normally cause such severe side effects! Nevertheless, the potential for very unpleasant interactions exists.

“Alternative therapies may have serious complications, and patients usually do not report them unless asked specifically,” the authors point out.

I am one-degree of separation from a patient whose femur (the big leg bone!) was fractured by a massage — it was a weak and injured femur already … but wow!

Nerves aren’t nearly as vulnerable to pressure as people generally think — most of them can actually take quite a licking and keep on ticking without a single symptom — but they aren’t invulnerable. And I once caused a nerve injury myself: it was a minor injury, but it did — augh — result in weeks of aggravating discomfort for my client. The Archives of Physical Medicine & Rehabilitation reported a similar spinal accesory nerve injury: “a rare and illustrative case of spinal accesory neuropathy associated with deep tissue massage leading to scapular winging [the shoulder blade sticking out] and droopy shoulder as a result of weakness of the trapezius muscle.”10
What Happened To My Barber? Either atlantoaxial instability or vertebrobasilar insufficiency causes severe dizziness and vomiting after massage therapy, with lessons for health care consumers ~ 2,750 words 

Lessons for professionals and patients

These are rare but real incidents. Healthy people are unlikely to be injured by massage. Most of dangers are related to undetected vulnerabilities, and they emphasize the importance of alternative health professionals being trained to spot the scary stuff. The measure of a health professional’s competence is not what they do with relatively healthy patients, but whether they have the training and humility to realize when they are on thin ice.

Manual therapists need to know that the most important part of their job is the smart management high-risk situations that they may see only a handful of times in their entire career. It’s like being on guard duty: 99.9% of the time, nothing bad happens. But how do you handle a curve ball when it finally comes?

Consumers need to know that cocky, overconfident therapists who trash-talk “mainstream” health care are all-too-likely to be ignorant of critical warning signs, or dismissive of them. The skeptical salamander thinks these therapists shouldn’t be allowed to touch anyone. See Missing Serious Symptoms.

About Paul Ingraham

I am a science writer, former massage therapist, and assistant editor of ScienceBasedMedicine.org. I have had my share of injuries and pain challenges as a runner and ultimate player. My wife and I live in downtown Vancouver, Canada. See my full bio and qualifications, or my blog, Writerly. You might run into me on Facebook and Google, but mostly Twitter.




Notes
Cambron JA, Dexheimer J, Coe P, Swenson R. Side-effects of massage therapy: a cross-sectional study of 100 clients. J Altern Complement Med. 2007 Oct;13(8):793–6. PubMed #17983334. BACK TO TEXT
 
Indeed, that seems very likely given the context. I doubt they would test painfully strong massage on 100 people without mentioning the intensity. However, painfully strong massage is quite common “in the wild.” Certainly intense massage is unusually common here in Vancouver, where there’s a regrettable professional predeliction for it. BACK TO TEXT
Ernst E. The Safety of Massage Therapy. Rheumatology. 2003;42 (9):1101–1106. PubMed #12777645. PainSci #54834.

Is massage safe? Researchers attempted to answer that question. Four databases were reviewed; all articles which reported adverse effects of any type of massage therapy were looked at. In the end, 20 reports were looked at. “The majority of adverse effects were associated with exotic types of manual massage or massage delivered by laymen, while massage therapists were rarely implicated.”

The conclusion was that, while not entirely risk free, “serious adverse events are probably true rarities.” BACK TO TEXT
Posadzki P, Ernst E. The safety of massage therapy: an update of a systematic review. Focus on Alternative and Complementary Therapies. 2013;18(1):27–32. PainSci #53974.


OBJECTIVE: To update a systematic review evaluating the safety of massage therapy.

METHODS: A literature search was carried out using four electronic databases for the period December 2001 to May 2012. All articles reporting adverse effects of massage therapy were retrieved. Adverse effects relating to atypical massage, aromatherapeutic massage oil or ice were excluded. No language restrictions were applied. Data were extracted and evaluated according to predefined criteria.

RESULTS: Seventeen case reports and one case series were published since our previous review. The reported adverse effects comprised acute paraplegia and abdominal distension, bladder rupture, bilateral cerebellar infarction, cervical lymphocele, cervical cord injury, cervical internal carotid and vertebral dissection, chylothorax, haematuria, interosseous nerve palsy, myopathy, perinephric haemorrhage, rhabdomyolysis, severe headache, blurred vision, paraesthesia and focal motor seizures. In the majority of the reports, a cause–effect relationship was certain or almost certain. Serious adverse effects were most commonly associated with massage techniques applied to the neck area.

CONCLUSION: Evidence suggests that massage may occasionally lead to moderately severe adverse effects. BACK TO TEXT
 
Several dozen at least who experienced minor negative effects and a lighter wallet. I recall only about dozen or so having really poor experiences, mostly aggravated chronic pain. Only a handful of those were obviously significantly injured by massage. But those were sad cases. BACK TO TEXT
 
Woolf CJ. Central sensitization: Implications for the diagnosis and treatment of pain. Pain. 2010 Oct;152(2 Suppl):S2–15. PubMed #20961685. PainSci #54851.

Pain itself often modifies the way the central nervous system works, so that a patient actually becomes more sensitive and gets more pain with less provocation. That sensitization is called “central sensitization” because it involves changes in the central nervous system (CNS) in particular — the brain and the spinal cord. Victims are not only more sensitive to things that should hurt, but also to ordinary touch and pressure as well. Their pain also “echoes,” fading more slowly than in other people.

For a much more detailed summary of this paper, see Central Sensitization in Chronic Pain. BACK TO TEXT
 
Lai MY, Yang SP, Chao Y, Lee PC, Lee SD. Fever with acute renal failure due to body massage-induced rhabdomyolysis. Journal of Nephrology, Dialysis and Transplantation. 2006 Jan;21(1):233–4. PubMed #16204282. PainSci #54301. BACK TO TEXT
 
Grant AC, Wang N. Carotid dissection associated with a handheld electric massager. South Med J. 2004 Dec;97(12):1262–3. PubMed #15646768. BACK TO TEXT
 
Tanriover MD, Guven GS, Topeli A. An unusual complication: prolonged myopathy due to an alternative medical therapy with heat and massage. South Med J. 2009 Sep;102(9):966–8. PubMed #19668045. BACK TO TEXT
 
Aksoy IA, Schrader SL, Ali MS, Borovansky JA, Ross MA. Spinal accessory neuropathy associated with deep tissue massage: a case report. Arch Phys Med Rehabil. 2009 Nov;90(11):1969–72. PubMed #19887226. BACK TO TEXT

https://www.painscience.com/articles/whats-the-harm.php

Epidural Steroid Injections For Neuropathy Warning! Vid

The problem with neuropathy is that it's one of those diseases which is impossible to cure and difficult to treat. This leaves the door open for desperate patients to try anything they may have seen advertised, or have heard about from friends. One of the current 'treatments' gaining popularity among neuropathy patients is the epidural steroid injection, despite the fact that it is being promoted as a treatment for severe back pain and not for the most common symptoms of neuropathy. Some people with neuropathy caused by impacted nerves or injury may benefit under controlled and expert conditions but it's dangerous to assume that it's beneficial for all forms of nerve damage. Today's Dr Oz clip warns about the dangers of these injections despite their being the number one treatment for lower back pain. They are not FDA approved and you should never go ahead with this sort of treatment if you have neuropathy and have not made the decision with the full agreement of a neurologist. The trouble is that people will clutch at straws when their symptoms are so severe. They will grab at a headline, read half a story and assume that such a treatment will be good for them. It's even more dangerous if unscrupulous clinics and doctors also misinform their patients in the search for easy earnings (as shown in the video). Forewarned is forearmed they say.



Epidural Steroid Injections, The Truth... Finally! / Part 1

The TRUTH about Epidural Injections. "If any good can come from this, in addition to shining a light on the need for greater oversight of compounding pharmacies, it might be that the media attention on steroid injections will allow patients to become better-informed consumers. For patients, it is buyer beware." Dr. Ray M. Baker, Anesthesiologist and President of the International Spine Intervention Society.

 

https://www.youtube.com/watch?v=QCbzXqrG0ic

Tapentadol A New Alternative For Neuropathic Pain

Today's post comes from marketwatch.com (see link below) and is a press release for Tapentadol, a new centrally-acting opioid made by Janssen Pharmceuticals to control neuropathic pain. Far be it from me to promote either a company or an opioid but we're always looking for alternatives to the treatments that either don't work, or have unpleasant side effects. This is another opium derivative, so there will undoubtedly be issues regarding side effects and addiction for some people but the tests look promising. The post is long because Janssen have provided a complete description of how the drug works and what the potential side effects may be and that's worth reading. One assumes that this information will all appear on the leaflet inside the box when the drug achieves general release. Tapentadol will not be for everybody, as is the case for all similar treatments but it may be a breakthrough for some. Time will tell.
More information about Tapentadol can be found here (and is easier to digest),

Phase 3 Data Show NUCYNTA® ER (tapentadol) Extended-Release Tablets Provide Pain Management for Patients with Diabetic Peripheral Neuropathy (DPN)

Study results presented at the 31st Annual Scientific Meeting of the American Pain Society

press release May 17, 2012,

RARITAN, N.J., May 17, 2012 /PRNewswire via COMTEX/ -- Janssen Pharmaceuticals, Inc. today announced the results of an investigational Phase 3 study suggesting NUCYNTA® ER (tapentadol) extended-release tablets were significantly more effective than placebo in providing pain management among adults with chronic moderate to severe, painful diabetic peripheral neuropathy (DPN). Results of the study were presented at the 31st Annual Scientific Meeting of the American Pain Society being held May 16-19 in Honolulu, Hawaii.

Diabetes affects nearly 26 million people in the United States(1)- and its prevalence is expected to grow significantly during the coming decades(2). Over time, people with diabetes can develop a type of nerve damage called neuropathy. Approximately 60 to 70 percent of people with diabetes have some form of neuropathy(3). The most common type is diabetic peripheral neuropathy, which causes pain or loss of feeling in the toes, feet, legs, hands, and arms.

The study found, among patients who had at least a one-point reduction in pain intensity during three weeks of treatment with tapentadol ER, those who continued on an optimized dose of tapentadol ER (100-250 mg twice daily) for an additional 12 weeks experienced significantly better pain control compared to those who switched to placebo(4). Treatment-emergent adverse events reported in 10 percent or more of tapentadol ER-treated patients during the double-blind maintenance period included nausea (21.1 percent) and vomiting (12.7 percent)(4).

"Painful DPN is a common and burdensome complication of diabetes, and controlling pain in people with DPN can be challenging," said Aaron I. Vinik, M.D., Ph.D., FCP, MACP, Director of Research and Neuroendocrine Unit at Strelitz Diabetes Center for Endocrine and Metabolic Disorders at Eastern Virginia Medical School, and lead investigator of the study. "These data suggest tapentadol ER provides a significant reduction in chronic pain in adult patients with DPN."

The findings of this study are consistent with those of another Janssen-sponsored study published early last year, which found tapentadol ER to be effective versus placebo for relieving moderate to severe chronic pain associated with diabetic peripheral neuropathy.

"We are pleased the Phase 3 data presented today showed tapentadol ER was effective at providing pain management for patients with chronic, moderate to severe pain associated with DPN," said Christine Rauschkolb, M.D., Ph.D., Vice President and Head of Integrated Operations, Janssen Research & Development, LLC and one of the study's authors. "Janssen has a long history of helping physicians provide responsible treatment for patients to relieve their acute and chronic pain. We are committed to developing new pain management options for the millions of Americans who have painful DPN."

About the Study

This Phase 3 clinical trial was a randomized-withdrawal, placebo-controlled study. It enrolled adult patients who had moderate to severe, chronic painful DPN for six months or more and a history of analgesic use for painful DPN for three months or more. This trial had three phases: an open-label phase, which included a 3-week titration period during which the individually optimized tapentadol ER dose (100-250 mg two times per day) was determined for each patient; a 12-week, double-blind maintenance phase, during which patients with a one-point or greater reduction in pain intensity from beginning to end of titration were randomized either to continue taking tapentadol ER (at their optimal dose) or to receive placebo; and a follow-up period with a clinic visit at four days and a telephone interview at 10 to 14 days after discontinuation of study drug.

The primary efficacy endpoint of the study was the mean change in average pain intensity from baseline (point of randomization) to the last week of the 12-week, double-blind maintenance phase, as determined by an 11-point pain rating scale or numerical rating scale (NRS; 0='no pain,' 10='pain as bad as you can imagine'). Safety assessments were performed on the open-label and double-blind safety populations (all patients who received greater than or equal to 1 dose of open-label and double-blind treatment, respectively). Treatment-emergent adverse events (TEAEs), defined as any AEs (new or worse in intensity) that occurred after the first intake of study drug during the open-label or double-blind phase, were monitored throughout the study.

In the open-label titration period, 459 patients received one or more doses of tapentadol ER and were included in the open-label safety population. At the start of the 3-week, open-label phase, the majority of patients (87.1 percent) reported severe pain (6 or more on the 11-point NRS) with a mean pain intensity of 7.3. By the end of the open-label phase, the mean pain intensity was reduced to 3.6. Treatment-emergent adverse events (TEAEs) experienced by 10 percent or more of patients during the open-label phase were nausea (24.4 percent), dizziness (17), constipation (11.8) and somnolence (10.7).

A total of 358 patients completed the open-label titration period; 318 were randomized and received one or more dose of study medication (n=152 for placebo, 166 for tapentadol ER).

Following randomization, during the double-blind treatment phase to week 12, pain increased in the placebo group (as demonstrated by the mean change in pain intensity of 1.3), while in the tapentadol ER group, efficacy was maintained, as indicated by the mean change in pain intensity of 0.28. The least-squares mean difference between the tapentadol ER and placebo groups in the change in average pain intensity was -0.95 on the 11-point NRS favoring tapentadol ER (95 percent CI, -1.42 to -0.49; p<0.001, tapentadol ER vs. placebo)(4).

For more details about the study design, please visit www.clinicaltrials.gov (NCT01041859).

Janssen Research & Development, LLC and Grunenthal GmbH, conducted this study, which Janssen Research & Development, LLC has included as part of its Supplemental New Drug Application (sNDA) submitted on October 28, 2011 to the U.S. Food and Drug Administration (FDA) for tapentadol ER tablets for the management of neuropathic pain associated with DPN in patients 18 years of age or older. The FDA currently is reviewing this supplemental application.

About Tapentadol and NUCYNTA® ER

Tapentadol is a centrally-acting synthetic analgesic. The tapentadol molecule is classified as Schedule II of the Controlled Substances Act.

NUCYNTA® ER (tapentadol) extended-release tablets are an oral analgesic available by prescription only and indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time. NUCYNTA® ER is taken twice daily and available in 50 mg, 100 mg, 150 mg, 200 mg and 250 mg strengths.

Outside the United States, tapentadol is marketed by Janssen Inc. in Canada; Grünenthal GmbH discovered tapentadol and markets immediate- and extended-release formulations of tapentadol (PALEXIA®) in various countries in Europe.

IMPORTANT SAFETY INFORMATION FOR NUCYNTA® ER (tapentadol) extended-release tablets

WARNING: POTENTIAL FOR ABUSE, PROPER PATIENT SELECTION, AND LIMITATIONS OF USE

Potential for Abuse

NUCYNTA® ER contains tapentadol, a mu-opioid agonist and a Schedule II controlled substance with an abuse liability similar to other opioid analgesics.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. These risks should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse, abuse, or diversion. Schedule II opioid substances, which include hydromorphone, morphine, oxycodone, fentanyl, oxymorphone, and methadone, have the highest potential for abuse and risk of fatal overdose due to respiratory depression.

Proper Patient Selection

NUCYNTA® ER is an extended-release formulation of tapentadol indicated for the management of moderate to severe chronic pain in adults when a continuous, around-the-clock opioid analgesic is needed for an extended period of time.

Limitations of Use

NUCYNTA® ER is not intended for use as an as-needed analgesic.

NUCYNTA® ER is not intended for the management of acute or postoperative pain.

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, dissolved, or crushed NUCYNTA® ER tablets could lead to rapid release and absorption of a potentially fatal dose of tapentadol.

Patients must not consume alcoholic beverages, or prescription or nonprescription medications containing alcohol. Co-ingestion of alcohol with NUCYNTA® ER may result in a potentially fatal overdose of tapentadol.

CONTRADICTIONS

NUCYNTA® ER is contraindicated in patients with significant respiratory depression, acute or severe bronchial asthma or hypercapnia in unmonitored settings or in the absence of resuscitative equipment.

NUCYNTA® ER is contraindicated in any patient who has or is suspected of having a paralytic ileus.

NUCYNTA® ER is contraindicated in patients who are receiving monoamine oxidase inhibitors (MAOIs) or who have taken them within the last 14 days due to potential additive effects on norepinephrine levels, which may result in adverse cardiovascular events.

NUCYNTA® ER is contraindicated in patients with a known hypersensitivity to the active substance, tapentadol, or any component of the product. Angioedema has been reported in association with use of tapentadol.

WARNINGS & PRECAUTIONS

NUCYNTA® ER tablets are to be swallowed whole and are not to be split, broken, chewed, dissolved, or crushed. Taking split, broken, chewed, crushed, or dissolved NUCYNTA® ER tablets leads to the rapid release and absorption of a potentially fatal dose of tapentadol.

NUCYNTA® ER tablets must be kept in a secure place out of the reach of children. Accidental consumption of NUCYNTA® ER, especially in children, can result in a fatal overdose of tapentadol.

Respiratory depression is the primary risk of mu-opioid agonists. Respiratory depression occurs more frequently in elderly or debilitated patients and in those suffering from conditions accompanied by hypoxia, hypercapnia, or upper airway obstruction, in whom even moderate therapeutic doses may significantly decrease pulmonary ventilation.

Use NUCYNTA® ER with caution in patients with conditions accompanied by hypoxia, hypercapnia, or decreased respiratory reserve, such as: asthma, chronic obstructive pulmonary disease or cor pulmonale, severe obesity, sleep apnea syndrome, myxedema, kyphoscoliosis, central nervous system (CNS) depression, or coma. In such patients, even usual therapeutic doses of NUCYNTA® ER may increase airway resistance and decrease respiratory drive to the point of apnea. Alternative non-mu-opioid agonist analgesics should be considered, and NUCYNTA® ER should be employed only under careful medical supervision at the lowest effective dose in such patients. If respiratory depression occurs, it should be treated as any mu-opioid agonist-induced respiratory depression.

Patients receiving other opioid agonist analgesics, general anesthetics, phenothiazines, other tranquilizers, sedatives, hypnotics, centrally acting muscle relaxants, or other CNS depressants (including alcohol) concomitantly with NUCYNTA® ER may exhibit additive CNS depression. Interactive effects resulting in respiratory depression, hypotension, profound sedation, coma, or death may result if these drugs are taken in combination with NUCYNTA® ER. When such combined therapy is contemplated, a dose reduction of one or both agents should be considered.

Opioid analgesics can raise cerebrospinal fluid pressure as a result of respiratory depression with carbon dioxide retention. Therefore, NUCYNTA® ER should not be used in patients who may be susceptible to the effects of raised cerebrospinal fluid pressure, such as those with evidence of head injury and increased intracranial pressure. Opioid analgesics may obscure the clinical course of patients with head injury due to effects on pupillary response and consciousness. NUCYNTA® ER should be used with caution in patients with head injury, intracranial lesions, or other sources of preexisting increased intracranial pressure.

Tapentadol is a mu-opioid agonist and is a Schedule II controlled substance. Such drugs are sought by drug abusers and people with addiction disorders. Diversion of Schedule II products is an act subject to criminal penalty.

Patients should be assessed for their clinical risks for opioid abuse or addiction prior to being prescribed opioids.

NUCYNTA® ER can be abused in a manner similar to other opioid agonists, legal or illicit. This should be considered when prescribing or dispensing NUCYNTA® ER in situations where the physician or pharmacist is concerned about an increased risk of misuse and abuse. Concerns about abuse and addiction should not prevent the proper management of pain. However, all patients treated with mu-opioid agonists require careful monitoring for signs of abuse and addiction, since use of mu-opioid agonist analgesic products carries the risk of addiction even under appropriate medical use.

Drug abusers may attempt to abuse NUCYNTA® ER by crushing, chewing, snorting, or injecting the product. These practices may result in the uncontrolled delivery of NUCYNTA® ER and pose a significant risk to the abuser that could result in overdose and death.

NUCYNTA® ER may cause severe hypotension. Patients at higher risk of hypotension include those with hypovolemia or those taking concurrent products that compromise vasomotor tone (eg, phenothiazines, general anesthetics).

Patients should be cautioned that NUCYNTA® ER may impair the mental and/or physical abilities required for the performance of potentially hazardous tasks such as driving a car or operating machinery. This is to be expected, especially at the beginning of treatment, at any change of dosage, as well as in combination with alcohol or tranquilizers.

NUCYNTA® ER may be expected to have additive effects when used in conjunction with alcohol, other opioids, or illicit drugs that cause CNS depression, because respiratory depression, hypotension, hypertension, and profound sedation, coma, or death may result.

NUCYNTA® ER has not been evaluated in patients with a predisposition to a seizure disorder, and such patients were excluded from clinical studies. As with other opioids, NUCYNTA® ER should be prescribed with care in patients with a history of a seizure disorder or any condition that would put the patient at risk of seizures.

Cases of life-threatening serotonin syndrome have been reported with the concurrent use of tapentadol and serotonergic drugs. Serotonergic drugs comprise selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, drugs that affect the serotonergic neurotransmitter system (eg, mirtazapine, trazodone, and tramadol), and drugs that impair metabolism of serotonin (including MAOIs). This may occur within the recommended dose. Serotonin syndrome may include mental-status changes (eg, agitation, hallucinations, coma), autonomic instability (eg, tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (eg, hyperreflexia, incoordination) and/or gastrointestinal symptoms (eg, nausea, vomiting, diarrhea), and can be fatal.

Withdrawal symptoms may occur if NUCYNTA® ER is discontinued abruptly. These symptoms may include: anxiety, sweating, insomnia, rigors, pain, nausea, tremors, diarrhea, upper respiratory symptoms, piloerection, and rarely, hallucinations. Withdrawal symptoms may be reduced by tapering NUCYNTA® ER.

A study with the immediate-release formulation of tapentadol in subjects with hepatic impairment showed higher serum concentrations of tapentadol than in those with normal hepatic function. Tapentadol should be used with caution in patients with moderate hepatic impairment.

NUCYNTA® ER has not been studied in patients with severe hepatic impairment, and use in this population is not recommended.

Like other drugs with mu-opioid agonist activity, NUCYNTA® ER may cause spasm of the sphincter of Oddi and should be used with caution in patients with biliary tract disease, including acute pancreatitis.

NUCYNTA® ER should be used with caution in the following conditions: adrenocortical insufficiency (eg, Addison's disease); delirium tremens; myxedema or hypothyroidism; prostatic hypertrophy or urethral stricture; and toxic psychosis.

Pregnancy Category C. There are no adequate and well-controlled studies of NUCYNTA® ER in pregnant women. NUCYNTA® ER should be used during pregnancy ONLY if the potential benefit justifies the potential risk to the fetus.

ADVERSE REACTIONS

The most common (greater than equal to 10%) adverse reactions were nausea, constipation, headache, dizziness, and somnolence.

About Janssen Pharmaceuticals, Inc. and Janssen Research and Development, LLC

At Janssen, we are dedicated to addressing and solving some of the most important unmet medical needs of our time in oncology, immunology, neuroscience, infectious diseases and vaccines, and cardiovascular and metabolic diseases. Driven by our commitment to patients, we develop and bring innovative products, services and solutions to people throughout the world.

Janssen Pharmaceuticals, Inc., and Janssen Research & Development, LLC are part of the Janssen Pharmaceutical Companies.

Janssen Pharmaceuticals, Inc. provides medicines for an array of health concerns in several therapeutic areas. Innovative therapies Janssen Pharmaceuticals, Inc. offers currently include ACIPHEX® (rabeprazole sodium), DORIBAX® (doripenem for injection), ELMIRON® (pentosan polysulfate sodium), NUCYNTA® (tapentadol), NUCYNTA® ER (tapentadol) extended-release tablets and XARELTO® (rivaroxaban) tablets. The full prescribing information for NUCYNTA® ER, including boxed warnings, is available here; the full prescribing information for XARELTO®, including boxed warnings, is available here.

For more information on Janssen Pharmaceuticals, Inc., visit us at www.janssenpharmaceuticalsinc.com or follow us on Twitter at www.twitter.com/JanssenUS .

For more information on Janssen Research & Development, LLC, visit us at http://www.janssenrnd.com/ .

http://www.marketwatch.com/story/phase-3-data-show-nucynta-er-tapentadol-extended-release-tablets-provide-pain-management-for-patients-with-diabetic-peripheral-neuropathy-dpn-2012-05-17

A New Alternative To Opiates For Nerve Pain

Today's post from consultqd.clevelandclinic.org (see link below) talks about a new advance in stem cell therapy concerning mesenchymal stem cells (MSC). These have been shown to reduce nerve pain and if they are injected directly into the vein, they have also been shown to reduce the side effects and addictiveness of opioids. Of course it's not as simple as this but these wonder cells apparently also can travel to the site of nerve injury and repair nerve cells on the spot. It may all seem a bit sci-fi and magical but it is true and reveals the huge potential of stem-cell therapy for all sorts of medical issues in the future. The fact that mesenchymal stem cells (MSC) directly apply to neuropathy problems makes it an exciting development for nerve pain patients across the world. Now we have to find the money in state budgets to develop the science and insurance companies who will pay for the treatment - don't hold your breath.

 Stem Cell Therapy for Neuropathic Pain: New Findings Show Promise
Animal studies demonstrate effectiveness

Aug. 10, 2016 / Pain Management / Research

Stem cell research at Cleveland Clinic could pave the way for an entirely new approach to chronic pain treatment that reduces medicine’s current reliance on opioid therapy for intractable pain. The modality also shows promise as a tool to reverse opioid tolerance (OT) and opioid-induced hyperalgesia (OIH), particularly problematic side effects of opioid therapy. Jianguo Cheng, MD, PhD, and his colleagues at Cleveland Clinic have developed patented methods of attenuating opioid tolerance.

Animal studies by Dr. Cheng and his colleagues have demonstrated the effectiveness of mesenchymal stem cell (MSC) transplantation in reducing hyperalgesia due to nerve injury. The group’s work has shown MSC transplantation’s effectiveness in reducing pain induced by sciatic nerve injury in rats and mice. MSC transplantation significantly reduced pain sensitivity evaluated by foot withdrawal thresholds in animals in response to thermal or mechanical stimulation. These cells produced immune modulatory and anti-inflammatory effects, promoted sensory nerve repair, and showed strong analgesic properties that could provide a safer and more effective alternative to current treatment modalities, in the management of neuropathic pain, says Dr. Cheng, Professor of Anesthesiology and Director of the Cleveland Clinic Multidisciplinary Pain Medicine Fellowship Program.

Pain medicine researchers are searching for an alternative to opioid therapy because neuropathic pain often does not respond to morphine and other opioids. Opioid analgesics can also lead to a variety of complications, ranging from itching and constipation to dependence, addiction, respiratory depression and death.

About 30 percent of neuropathy cases are caused by nerve damage associated with diabetes. However, hundreds of diseases are linked to neuropathic pain. Sources of neuropathic pain include alcoholism, amputation (which can result in phantom pain), some chemotherapy drugs (for example, Cisplatin®, Paclitaxel®, Vincristine®), radiation therapy, complex regional pain syndrome type II, trigeminal neuralgia, shingles, spinal stenosis, and central nervous system disorders, such as Parkinson disease and multiple sclerosis.

Recent research by Dr. Cheng and his group has yielded new discoveries that bode well for MSC transplantation as a potential future treatment modality. One investigation compared the analgesic effects of MSC derived from bone marrow with MSC derived from adipose tissue. Adipose-derived cells were found to be as efficacious as bone marrow-derived cells in reducing neuropathic pain in rats. The finding suggests that stem cell therapy could offer a practical option because stem cells from adipose tissue are relatively easy to obtain.

Recent investigations by Dr. Cheng and his colleagues comparing the analgesic effectiveness of intrathecal versus intravenous methods of MSC transplantation show both methods to be equally effective. The finding has important implications because intravenous transplantation of MSC could offer a safer and more expeditious route of delivery than intrathecal transplantation.

“We originally thought that stem cells would have to be introduced intrathecally in order to reduce pain, and that stem cells introduced intravenously would pass through the lungs and fail to produce analgesia,” says Dr. Cheng. “The finding that intravenous transplantation is as effective as intrathecal transplantation is encouraging.”

Dr. Cheng’s group has also discovered that MSCs can be found in the area surrounding the injured nerve following MSC transplantation. “For reasons we do not yet fully understand, these cells have the ability to migrate to the injury site to promote repair of the injured nerve fibers,” Dr. Cheng says. “The cells can sense the injury’s location and travel to it.”

Although many questions must be answered before it can be known whether stem cell therapy is safe and effective for humans, some small patient studies show potential, Dr. Cheng says. According to one observational study in Australia, MSC transplantation reduced pain in patients suffering from trigeminal neuralgia, a particularly difficult condition to treat. “Though the findings are preliminary, the study provides some evidence that what we have learned in the laboratory can be translated to clinical use,” Dr. Cheng says.

Dr. Cheng’s team has achieved analgesia with MSC transplantation from rats to mice, providing early evidence that stem cells’ anti-inflammatory and immuno-modulatory properties can be transferred between species. An important pre-clinical study will be to see whether the transplantation of human stem cells to animals also can produce analgesic and anti-tolerance effects, Dr. Cheng says.

Dr. Cheng’s team presented research at the 2016 annual meeting of the American Academy of Pain Medicine showing MSC’s potential to reverse opioid tolerance and opioid-induced hyperalgesia, problems that can compromise the safety and efficacy of opioid therapy. Intravenous transplantation of bone marrow-derived MSC significantly attenuated OT and OIH in animals whether the transplantation was performed seven days before or 14 days after the initiation of daily morphine injections. These data demonstrate that MSC transplantation can not only prevent the development of OT and OIH but can also reverse it.

https://consultqd.clevelandclinic.org/2016/08/stem-cell-therapy-neuropathic-pain-new-findings-show-promise/